Spiro-azacyclic derivatives, their preparation and their use as tachykinin antagonists

ABSTRACT

The present invention relates to certain spiro-azacyclic derivatives which are tachykinin antagonists and are useful, for example, in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.

This invention relates to a class of azacyclic compounds which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention are spiro-substituted azacyclic derivatives.

International (PCT) patent specification no. WO 94/20500 (published Sep.15th, 1994) discloses spiroazacyclic derivatives as substance Pantagonists. In particular, WO 94/20500 relates to spirocyclicpiperidine derivatives containing a 1,8-diazaspiro[5.5]undecane core.

We have now found a further class of non-peptides which are potentantagonists of tachykinins, especially of substance P.

The present invention provides compounds of the formula (I): ##STR1##wherein

R¹ represents hydrogen, hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, fluoroC₁₋₆ alkyl, C₁₋₆ alkoxy,fluoroC₁₋₆ alkoxy, C₁₋₆ alkoxyC₁₋₄ alkyl, C₁₋₆ alkoxyC₁₋₄ alkoxy,fluoroC₁₋₆ alkoxyC₁₋₄ alkyl, C₂₋₆ alkenyloxy, C₃₋₇ cycloalkoxy, C₃₋₇cycloalkylC₁₋₄ alkoxy, phenoxy, benzyloxy, cyano, halogen, NR¹¹ COR¹⁴,NR^(a) R^(b), SR^(a), SOR^(a), SO₂ R^(a), OSO₂ R^(a), or C₁₋₄ alkylsubstituted by cyano or CO₂ R^(a), where R^(a) and R^(b) eachindependently represent hydrogen, C₁₋₄ alkyl or fluoroC₁₋₄ alkyl;

R² represents hydrogen, halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

or when R² is adjacent to R¹, they may be joined together such thatthere is formed a 5- or 6-membered saturated or unsaturated ringcontaining one or two oxygen atoms;

R³ represents a 5- or 6-membered aromatic heterocyclic group containing1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur,which group is optionally substituted by one or two groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, SR^(a), SOR^(a),SO₂ R^(a), COR^(a), CO₂ R^(a), phenyl, --(CH₂)_(r) NR^(a) R^(b),--(CH₂)_(r) NR^(a) COR^(b), --(CH₂)_(r) CONR^(a) R^(b), or CH₂C(O)R^(a), where R^(a) and R^(b) are each independently hydrogen or C₁₋₄alkyl and r is zero, 1 or 2;

R⁴ represents hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,trifluoromethyl, trifluoromethoxy, nitro, cyano, SR^(a), SOR^(a), SO₂R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄alkyl substituted by C₁₋₄ alkoxy, where R^(a) and R^(b) eachindependently represent hydrogen or C₁₋₄ alkyl;

R⁵ represents hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl or C₁₋₆alkoxy substituted by C₁₋₄ alkoxy;

R⁶ represents hydrogen, COR^(a), CO₂ R^(a), COCONR^(a) R^(b), COCO₂R^(a), C₁₋₆ alkyl optionally substituted by a group selected from (CO₂R^(a), CONR^(a) R^(b), hydroxy, cyano, COR^(a), NR^(a) R^(b),C(NOH)NR^(a) R^(b), CONHphenyl(C₁₋₄ alkyl), COCO₂ R^(a), CONHNR^(a)R^(b), C(S)NR^(a) R^(b), CONR^(a) C₁₋₆ alkylR¹², CONR¹³ C₂₋₆ alkenyl,CONR¹³ C₂₋₆ alkynyl, COCONR^(a) R^(b), CONR^(a) C(NR^(b))NR^(a) R^(b),CONR^(a) heteroaryl, and phenyl optionally substituted by one, two orthree substituents selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen andtrifluoromethyl), where R^(a) and R^(b) are each independently hydrogenor C₁₋₄ alkyl;

or R⁶ represents a group of the formula --CH₂ C.tbd.CCH₂ NR⁷ R⁸ where R⁷and R⁸ are as defined below;

or R⁶ represents C₁₋₆ alkyl, optionally substituted by oxo, substitutedby a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3nitrogen atoms optionally substituted by ═O or ═S and optionallysubstituted by a group of the formula ZNR⁷ R⁸ where

Z is C₁₋₆ alkylene or C₃₋₆ cycloalkyl;

R⁷ is hydrogen or C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy or hydroxyl;

R⁸ is hydrogen or C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy, hydroxyl or a 4, 5 or 6membered heteroaliphatic ring containing one or two heteroatoms selectedfrom N, O and S;

or R⁷, R⁸ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by oneor two groups selected from hydroxy or C₁₋₄ alkoxy optionallysubstituted by a C₁₋₄ alkoxy or hydroxyl group, and optionallycontaining a double bond, which ring may optionally contain an oxygen orsulphur ring atom, a group S(O) or S(O)₂ or a second nitrogen atom whichwill be part of a NH or NR^(c) moiety where R^(c) is C₁₋₄ alkyloptionally substituted by hydroxy or C₁₋₄ alkoxy;

or R⁷, R⁸ and the nitrogen atom to which they are attached form anon-aromatic azabicyclic ring system of 6 to 12 ring atoms;

or Z, R⁷ and the nitrogen atom to which they are attached form aheteroaliphatic ring to 4 to 7 ring atoms which may optionally containan oxygen ring atom;

R⁹ and R¹⁰ each independently represent hydrogen, halogen, C₁₋₆ alkyl,CH₂ OR^(d), oxo, CO₂ R^(a) or CONR^(a) R^(b) where R^(a) and R^(b) areeach independently hydrogen or C₁₋₆ alkyl and R^(d) represents hydrogen,C₁₋₆ alkyl or phenyl;

R¹¹ represents hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy orhydroxyl;

R¹² represents OR^(a), CONR^(a) R^(b) or heteroaryl, where R^(a) andR^(b) are each independently hydrogen or C₁₋₄ alkyl;

R¹³ represents H or C₁₋₆ alkyl;

R¹⁴ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, fluoroC₁₋₆ alkyl or phenyl;

p is zero or 1;

q is 1 or 2; and

X represents --CH₂ -- or --CH₂ CH₂ --;

Y represents --CH═, --CH₂ --, --CH₂ CH═ or --CH₂ CH₂ --, with theproviso that the sum total of carbon atoms in X+Y is 2 or 3; and

when X is --CH₂ -- and Y is --CH═ or --CH₂ CH═, the broken linerepresents a double bond;

and pharmaceutically acceptable salts thereof.

One particular sub-class of compound of formula (I) is that wherein: R¹represents C₁₋₆ alkyl, C₁₋₆ alkoxy, fluoroC₁₋₆ alkyl, fluoroC₁₋₆ alkoxy,C₁₋₆ alkoxyC₁₋₄ alkyl, C₁₋₆ alkoxyC₁₋₄ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇cycloalkoxy, C₃₋₇ cycloalkylC₁₋₄ alkyl, C₃₋₇ cycloalkylC₁₋₄ alkoxy,halogen, cyano or --NR¹¹ COCF₃ ;

and pharmaceutically acceptable salts thereof.

A particularly preferred class of compound of formula (I) is thatwherein R¹ is a methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy ortrifluoromethoxy group, especially a trifluoromethoxy group.

Another preferred class of compound of formula (I) is that wherein R² isa hydrogen, fluorine or chlorine atom, especially a hydrogen atom.

A further preferred class of compound of formula (I) is that wherein R⁴is a hydrogen atom or a fluorine atom.

Another preferred class of compound of formula (I) is that in which R⁵is a hydrogen atom.

Also preferred is the class of compound of formula (I) in which R⁹ andR¹⁰ are both hydrogen atoms.

A further preferred class of compound of formula (I) is that wherein R⁶is a hydrogen atom.

Also preferred is the class of compound of formula (I) in which R⁶ is aC₁₋₆ alkyl group, in particular CH₂, CH(CH₃) and CH₂ CH₂ and especiallyCH₂, substituted by a 5-membered heterocyclic ring containing 2 or 3nitrogen atoms as previously defined.

In particular, the 5-membered ring is a heterocyclic ring selected from:##STR2##

Particularly preferred heterocyclic rings are selected from: ##STR3##

Most especially, the heterocyclic ring is selected from: ##STR4##

A particularly preferred heterocyclic ring is: ##STR5##

Preferably the double bond represented by the broken line is absent.

Where R¹ and R² are attached to adjacent carbon atoms and are joinedtogether such that there is formed a 5- or 6-membered saturated orunsaturated ring containing one or two oxygen atoms, there is formed afused ring moiety such as 2,3-dihydrobenzofuran, benzofuran,3,4-dihydro-2H-1-benzopyran, 2H-1-benzopyran, 1,3-benzodioxole or1,4-benzodioxan. Particularly preferred is 2,3-dihydrobenzofuran wherethe oxygen atom corresponds to the position of R¹.

Certain particularly apt compounds of the present invention includethose wherein R³ is a group selected from pyrrole, furan, thiene,pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole,thiadiazole, triazine, and tetrazole, each heteroaryl group beingoptionally substituted as previously defined.

Preferred compounds of the present invention are those wherein R³ is agroup selected from furan, pyridine, pyrazole, imidazole, oxazole,isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole,1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, eachheteroaryl group being optionally substituted as previously defined.

Particularly preferred compounds of the present invention are thosewherein R³ is a group selected from furan, pyridine, pyrimidine,1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl groupbeing optionally substituted as previously defined.

Another preferred class of compounds of the present invention is thatwherein R³ is a group selected from tetrazole, furan, thiazole, thiene,pyridine, oxazole, pyrazine and pyrimidine, each heteroaryl group beingoptionally substituted as previously defined.

A further preferred class of compounds of the present invention is thatwherein R³ is a group selected form tetrazole, furan, thiazole, thiene,pyridine, oxazole, pyrazole, pyrimidine and isoxazole, each heteroarylgroup being optionally substituted as previously defined.

Preferably, the group R³ is unsubstituted or substituted by one or twogroups selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano,SR^(a), SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a), phenyl, --(CH₂)_(r)NR^(a) R^(b), --(CH₂)_(r) NR^(a) COR^(b), --(CH₂)_(r) CONR^(a) R^(b) orCH₂ C(O)R^(a) where R^(a) and R^(b) are each independently hydrogen orC₁₋₄ alkyl, and r is zero, 1 or 2.

A particularly preferred class of compound is that wherein the group R³is unsubstituted or monosubstituted. Particularly preferredsubstitutents on the group R³ are halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃,OCF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a),--(CH₂)_(r) CONR^(a) R^(b), (CH₂)_(r) NR^(a) R^(b), and (CH₂)_(r) NR^(a)COR^(b) where R^(a) and R^(b) are as previously defined. Especiallypreferred substituents (when present) are C₁₋₄ alkyl, especially methyl,and trifluoromethyl.

An especially preferred class of compound of formula (I) is that whereinR³ is the group ##STR6## where R¹¹ is hydrogen, halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, OCF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), COR^(a),CO₂ R^(a), (CH₂)_(r) CONR^(a) R^(b), (CH₂)_(r) NR^(a) R^(b) or (CH₂)_(r)NR^(a) COR^(b), where R^(a) and R^(b) are hydrogen or C₁₋₄ alkyl, and ris zero, 1 or 2.

Another especially preferred class of compound of formula (I) is thatwherein R³ is the group ##STR7## wherein R¹¹ is as previously defined.

R¹¹ is preferably hydrogen, C₁₋₄ alkyl, especially methyl, or CF₃.

Preferably p is zero.

Preferably q is 2.

Preferably X is --CH₂ --.

Preferably Y is --CH₂ -- or --CH═.

One favoured group of compounds of the present invention are of theformula (Ia) and pharmaceutically acceptable salts thereof: ##STR8##wherein R¹, R², R³, R⁴, R⁹, R¹⁰ and the broken line are as defined inrelation to formula (I).

Another favoured group of compounds of the present invention are of theformula (Ib) and pharmaceutically acceptable salts thereof: ##STR9##wherein R¹, R², R³, R⁴, R⁹ and R¹⁰ are as defined in relation to formula(I).

With respect to compounds of the formula (I), Z (where present), may bea linear, branched or cyclic group. Favourably Z contains 1 to 4 carbonatoms and most favourably 1 or 2 carbon atoms. A particularly favourablegroup Z is CH₂.

With respect to compounds of the formula (I), R⁷ may aptly be a C₁₋₄alkyl group or a C₂₋₄ alkyl group substituted by a hydroxyl or C₁₋₂alkoxy group, R⁸ may aptly be a C₁₋₄ alkyl group or a C₂₋₄ alkyl groupsubstituted by a hydroxyl or C₁₋₂ alkoxy group, or R⁷ and R⁸ may belinked so that, together with the nitrogen atom to which they areattached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino,thiomorpholino, piperazine or piperazino group substituted on thenitrogen atom by a C₁₋₄ alkyl group or a C₂₋₄ alkyl group substituted bya hydroxy or C₁₋₂ alkoxy group.

Where the group NR⁷ R⁸ represents a heteroaliphatic ring of 4 to 7 ringatoms and said ring contains a double bond, a particularly preferredgroup is 3-pyrroline.

Where the group NR⁷ R⁸ represents a non-aromatic azabicyclic ringsystem, such a system may contain between 6 and 12, and preferablybetween 7 and 10, ring atoms. Suitable rings include5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl,6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl,6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl,6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.1]decyl,7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.

Where R⁸ represents a C₂₋₄ alkyl group substituted by a 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S, suitable rings include pyrrolidino, piperidino, piperazino,morpholino, or thiomorpholino. Particularly preferred are nitrogencontaining heteroaliphatic rings, especially pyrrolidino and morpholinorings.

In the group ZNR⁷ R⁸, Z is preferably CH₂ or CH₂ CH₂, and especiallyCH₂.

The group NR⁷ R⁸ preferably represents amino, methylamino,dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.

In particular, NR⁷ R⁸ is preferably dimethylamino, azetidinyl orpyrrolidino, especially dimethylamino.

As used herein, the term "alkyl" or "alkoxy" as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the terms "fluoroC₁₋₆ alkyl" and fluoroC₁₋₆ alkoxy"means a C₁₋₆ alkyl or C₁₋₆ alkoxy group in which one or more (inparticular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms.Similarly the term "fluoroC₁₋₄ alkyl" means a C₁₋₄ alkyl group in whichone or more (in particular, 1 to 3) hydrogen atoms have been replaced byfluorine atoms. Particularly preferred are fluoroC₁₋₃ alkyl andfluoroC₁₋₃ alkoxy groups, for example, CF₃, CH₂ CH₂ F, CH₂ CHF₂, CH₂CF₃, OCF₃, OCH₂ CH₂ F, OCH₂ CHF₂ or OCH₂ CF₃, and most especially CF₃,and OCF₃.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitablecycloalkylalkyl group may be, for example, cyclopropylmethyl.

As used herein, the terms "alkenyl" and "alkynyl" as a group or part ofa group means that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is propargyl.

As used herein, the term "heteroaryl" as a group or part of a groupmeans a 5- or 6-membered heteroaromatic ring containing 1 to 4heteroatoms selected from N, O and S. Particular examples of such groupsinclude pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, andtetrazolyl.

When used herein the term "halogen" means fluorine, chlorine, bromineand iodine. The most apt halogens are fluorine and chlorine of whichfluorine is preferred, unless otherwise stated.

Specific compounds within the scope of this invention include:

(6S,5R)-3-(5-methoxy-2-(5-trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;

(6S,5R,3S)-3-(5-methoxy-2-(5-trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;

(6S,5R)-3-(5-methoxy-2-(tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;

(6S,5R,3S)-3-(5-methoxy-2-(tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;;

and pharmaceutically acceptable salts thereof.

Further preferred compounds within the scope of this invention include:

(5R,6S)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene;

(3S,5R,6S)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;

(3S,5R,6S)-6-phenyl-3-(2-(thiazol-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;

(3S,5R,6S)-6-phenyl-3-(2-(thien-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-3-(2-(fur-3-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-6-phenyl-3-(2-(pyrid-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-6-phenyl-3-(2-(pyrid-3-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-6-phenyl-3-(2-(pyrid-4-yl)-5-(trifluoromethoxy))phenyl-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-6-phenyl-3-(2-(oxazol-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-6-phenyl-3-(2-(pyrazin-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-6-phenyl-3-(2-(pyrimidin-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;

(3R,5R,6S)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;

and pharmaceutically acceptable salts thereof.

In a further aspect of the present invention, the compounds of formula(I) may be prepared in the form of a pharmaceutically acceptable salt,especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid. p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid. tartaric acid, carbonic acid, phosphoric acid or sulphuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the "parent drug" or "parent molecule")that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The compounds of the formula (I), (Ia) and (Ib) will have the preferredstereochemistry of the 5- and 6-positions that is possessed by thecompound of Example 1 (i.e. 5-(R) and 6-(S)). Thus for example as shownin formula (Ic) ##STR10##

A particularly preferred class of compound of the formula (I), (Ia),(Ib) and (Ic) is that where the double bond represented by the brokenline is absent and the stereochemistry of the 3-position is 3-(R).

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination, andapply to the generic formula for compounds of the prsent invention aswell as to the preferred classes of compound represented by formulae(Ia), (Ib) and (Ic).

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such a corn starch lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas trgacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose polyvinyl-pyrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a compound of formula (I), as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

Suitable surface-active agents include, in particular, non-ionic agents,such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) andother sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g. egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example glycerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsion swill typically contain up to 20% oil, forexample, between 5 and 20%. the fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared bymixing a compound of formula (I) with Intralipid™ or the componentsthereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention futher provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity.

Thus, for example, an excess of tachykinin, and in particular substanceP, activity is implicated in a variety of disorders of the centralnervous system. Such disorders include mood disorders, such asdepression or more particularly depressive disorders, for example,single episodic or recurrent major depressive disorders and dysthymicdisorders, or bipolar disorders, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder; anxiety disorders, such aspanic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobias, for example, specific animalphobias, social phobias, obsessive-compulsive disorder, stress disordersincluding post-traumatic stress disorder and acute stress disorder, andgeneralised anxiety disorders; schizophrenia and other psychoticdisorders, for example, schizophreniform disorders, schizoaffectivedisorders, delusional disorders, brief psychotic disorders, sharedpsychotic disorders and psychotic disorders with delusions orhallucinations; delerium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Alzheimer's disease, seniledementia, dementia of the Alzheimer's type, vascular dementia, and otherdementias, for example, due to HIV disease, head trauma, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeldt-Jakobdisease, or due to multiple aetiologies; Parkinson's disease and otherextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremour; substance-relateddisorders arising from the use of alcohol, amphetamines (oramphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens,inhalants and aerosol propellants, nicotine, opioids, phenylglycidinederivatives, sedatives, hypnotics, and anxiolytics, whichsubstance-related disorders include dependence and abuse, intoxication,withdrawal, intoxication delerium, withdrawal delerium, persistingdementia, psychotic disorders, mood disorders, anxiety disorders, sexualdysfunction and sleep disorders; epilepsy; Down's syndrome;demyelinating diseases such as MS and ALS and other neuropathologicaldisorders such as peripheral neuropathy, for example diabetic andchemotherapy-induced neuropathy, and postherpetic neuraligia, trigeminalneuralgia, segmental or intercostal neuralgia and other neuralgias; andcerebral vascular disorders due to acute or chronic cerebrovasculardamage such as cerebral infarction, subarachnoid haemorrhage or cerebraloedema.

Tachykinin, and in particular substance P, activity is also involved innociception and pain. The compounds of the present invention willtherefore be of use in the prevention or treatment of diseases andconditions in which pain predominates, including soft tissue andperipheral damage, such as acute trauma, osteoarthritis, rheumatoidarthritis, musculo-skeletal pain, particularly after trauma, spinalpain, dental pain, myofascial pain syndromes, headache, episiotomy pain,and burns; deep and visceral pain, such as heart pain, muscle pain, eyepain, orofacial pain, for example odontalgia, abdominal pain,gynaecological pain, for example, dysmenorrhoea, and labour pain; painassociated with nerve and root damage, such as pain associated withperipheral nerve disorders, for example, nerve entrapment and brachialplexus avulsions, amputation, peripheral neuropathies, tic douloureux,atypical facial pain, nerve root damage, and arachnoiditis, painassociated with carcinoma, often referred to as cancer pain; centralnervous system pain, such as pain due to spinal cord or brain stemdamage; low back pain; sciatica; ankylosing spondylitis, gout; and scarpain.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, adult respiratory distress syndrome, and bronchospasm;inflammatory diseases such as inflammatory bowel disease, psoriasis,fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;allergies such as eczema and rhinitis; hypersensitivity disorders suchas poison ivy; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; ophthalmic conditions associated with cellproliferation such as proliferative vitreoretinopathy; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of neoplasms, including breast tumours,neuroganglioblastomas and small cell carcinomas such as small cell lungcancer.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of gastrointestinal (GI) disorders, includinginflammatory disorders and diseases of the GI tract such as gastritis,gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disordersassociated with the neuronal control of viscera, ulcerative colitis,Crohn's disease, irritable bowel syndrome and emesis, including acute,delayed or anticipatory emesis such as emesis induced by chemotherapy,radiation, toxins, viral or bacterial infections, pregnancy, vestibulardisorders, for example, motion sickness, vertigo, dizziness andMeniere's disease, surgery, migraine, variations in intercranialpressure, gastro-oesophageal reflux disease, acid indigestion, overindulgence in food or drink, acid stomach, waterbrash or regurgitation,heartburn, for example, episodic, nocturnal or meal-induced heartburn,and dyspepsia.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of a variety of other conditions including stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus; plasmaextravasation resulting from cytokine chemotherapy, disorders of bladderfunction such as cystitis, bladder detrusor hyper-reflexia andincontinence; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of blood flow caused byvasodilation and vasospastic diseases such as angina, vascular headache,migraine and Reynaud's disease; and pain or nociception attributable toor associated with any of the foregoing conditions, especially thetransmission of pain in migraine.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofemesis, including acute, delayed or anticipatory emesis, such as emesisinduced by chemotherapy, radiation, toxins, pregnancy, vestibulardisorders, motion, surgery, migraine, and variations in intercranialpressure. Most especially, the compounds of formula (I) are of use inthe treatment of emesis induced by antineoplastic (cytotoxic) agents,including those routinely used in cancer chemotherapy, and emesisinduced by other pharmacological agents, for example, rolipram.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in Nausea and Vomiting: Recent Research andClinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton,Fla., USA (1991) pages 177-203, especially page 188. Commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubincin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil [R. J. Gralla et al. in Cancer TreatmentReports (1984) 68(1), 163-172].

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula (I) in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide or domperidone, orGABA_(B) receptor agonists such as baclofen. Additionally, a compound offormula (I) either alone or in combination with one or more otheranti-emetic therapeutic agents, may be administered in combination withan anti-inflammatory corticosteroid, such as dexamethasone,betamethasone, triamcinolone, triamcinolene acetonide, flunisolide,budesonide, or others such as those disclosed in U.S. Pat. Nos.2,789,118, 2,99,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359,3,928,326 and 3,748,712. Dexamethasone (Decadron™) is particularlypreferred. Furthermore, a compound of formula (I) may be administered incombination with a chemotherapeutic agent such as an alkylating agent,antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as describedabove. In general, the currently available dosage forms of the knowntherapeutic agents for use in such combinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and headache includingmigraine, acute or chronic tension headache, cluster headache,temporomandibular pain and maxillary sinus pain.

The compounds of formula (I) are also particularly useful in thetreatment of depression including depressive disorders, for example,single episodic or recurrent major depressive disorders, and dysthymicdisorders, depressive neurosis, and neurotic depression; melancholicdepression including anorexia, weight loss, insomnia and early morningwaking, and psychomotor retardation; atypical depression (or reactivedepression) including increased appetite, hypersomnia, psychomotoragitation or irritability, anxiety and phobias; seasonal affectivedisorder; or bipolar disorders or manic depression, for example, bipolarI disorder, bipolar II disorder and cyclothymic disorder.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor agonist or tachykinin antagonist which acts at NK-2 receptors.The compound of formula (I) and the bronchodilator may be administeredto a patient simultaneously, sequentially or in combination.

Likewise, a compound of the present invention may be employed with aleukotriene antagonists, such as a leukotriene D₄ antagonist such as acompound selected from those disclosed in European patent specificationnos. 0 480 717 and 0 604 114 and in U.S. Pat. No. 4,859,692 and5,270,324. This combination is particularly useful in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and cough.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

Likewise, for the treatment of behavioural hyperalgesia, a compound ofthe present invention may be used in conjunction with an antagonist ofN-methyl D-aspartate (NMDA), such as dizocilpine.

For the treatment or prevention of inflammatory conditions in the lowerurinary tract, especially cystitis, a compound of the present inventionmay be used in conjunction with an antiinflammatory agent such as abradykinin receptor antagonist.

It will be appreciated that for the treatment or prevention of pain ornociception, a compound of the present invention may be used inconjunction with other analgesics, such as acetaminophen (paracetamol),aspirin and other NSAIDs and, in particular, opioid analgesics,especially morphine. Specific anti-inflammatory agents includediclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam andsulindac. Suitable opioid analgesics of use in conjunction with acompound of the present invention include morphine, codeine,dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone,levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol,fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxypheneand pentazocine; or a pharmaceutically acceptable salt thereof.Preferred salts of these opioid analgesics include morphine sulphate,morphine hydrochloride, morphine tartrate, codeine phosphate, codeinesulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride,hydrocodone bitartrate, hydromorphone hydrochloride, levorphanoltartrate, oxymorphone hydrochloride, alfentanil hydrochloride,buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate,meperidine hydrochloride, methadone hydrochloride, nalbuphinehydrochloride, propoxyphene hydrochloride, propoxyphene napsylate(2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocinehydrochloride.

Therefore, in a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention and an analgesic, together with at least onepharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there isprovided a product comprising a compound of the present invention and ananalgesic as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of pain or nociception.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents.

Suitable classes of anti-depressant agent include norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists and atypical anti-depressants.

Suitable norepinephrine reuptake inhibitors include tertiary aminetricyclics and secondary amine tricyclics. Suitable examples of tertiaryamine tricyclics include: amitriptyline, clomipramine, doxepin,imipramine and trimipramine, and pharmaceutically acceptable saltsthereof. Suitable examples of secondary amine tricyclics include:amoxapine, desipramine, maprotiline, nortriptyline and protriptyline,and pharmaceutically acceptable salts thereof.

Suitable selective serotonin reuptake inhibitors include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable monoamine oxidase inhibitors include: isocarboxazid,phenelzine, tranylcypromine and selegiline, and pharmaceuticallyacceptable salts thereof.

Suitable reversible inhibitors of monoamine oxidase include:moclobemide, and pharmaceutically acceptable salts thereof.

Suitable serotonin and noradrenaline reuptake inhibitors of use in thepresent invention include: venlafaxine, and pharmaceutically acceptablesalts thereof.

Suitable CRF antagonists include those compounds described inInternational Patent Specification Nos. WO 94/13643, WO 94/13644, WO94/13661, WO 94/13676 and WO 94/13677.

Suitable atypical anti-depressants include: bupropion, lithium,nefazodone, trazodone and viloxazine, and pharmaceutically acceptablesalts thereof.

Suitable classes of anti-anxiety agent include benzodiazepines and5-HT_(1A) agonists or antagonists, especially 5-HT_(1A) partialagonists, and corticotropin releasing factor (CRF) antagonists.

Suitable benzodiazepines include: alprazolam, chlordiazepoxide,clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam andprazepam, and pharmaceutically acceptable salts thereof.

Suitable 5-HT_(1A) receptor agonists or antagonists include, inparticular, the 5-HT_(1A) receptor partial agonists buspirone,flesinoxan, gepirone an dopsapirone, and pharmaceutically acceptablesalts thereof.

Therefore, in a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention and an anti-depressant or anti-anxiety agent, togetherwith at least one pharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there isprovided a product comprising a compound of the present invention and ananti-depressant or anti-anxiety agent as a combined preparation forsimultaneous, separate or sequential use for the treatment or preventionof depression and/or anxiety.

It will be appreciated that for the treatment or prevention of eatingdisorders, including obesity, bulimia nervosa and compulsive eatingdisorders, a compound of the present invention may be used inconjunction with other anorectic agents.

The present invention accordingly provides the use of a compound offormula (I) and an anorectic agent for the manufacture of a medicamentfor the treatment or prevention of eating disorders.

The present invention also provides a method for the treatment orprevention of eating disorders, which method comprises administration toa patient in need of such treatment an amount of a compound of formula(I) and an amount of an anorectic agent, such that together they giveeffective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I) and ananorectic agent, together with at least one pharmaceutically acceptablecarrier or excipient.

It will be appreciated that the compound of formula (I) and anorecticagent may be present as a combined preparation for simultaneous,separate or sequential use for the treatment or prevention of eatingdisorders. Such combined preparations may be, for example, in the formof a twin pack.

In a further or alternative aspect of the present invention, there istherefore provided a product comprising a compound of formula (I) and ananorectic agent as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of eating disorders.

In a further embodiment of the present invention there is provided theuse of a compound of formula (I) and an anorectic agent for themanufacture of a medicament for the treatment or prevention of obesity.

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of formula (I)and an amount of an anorectic agent, such that together they giveeffective relief.

In an alternative embodiment of the present invention there is providedthe use of a compound of formula (I) and an anorectic agent for themanufacture of a medicament for the treatment or prevention of bulimianervosa.

The present invention also provides a method for the treatment orprevention of bulimia nervosa, which method comprises administration toa patient in need of such treatment an amount of a compound of formula(I) and an amount of an anorectic agent, such that together they giveeffective relief.

In a further embodiment of the present invention there is provided theuse of a compound of formula (I) and an anorectic agent for themanufacture of a medicament for the treatment or prevention ofcompulsive eating disorders.

The present invention also provides a method for the treatment orprevention of compulsive eating disorders, which method comprisesadministration to a patient in need of such treatment an amount of acompound of formula (I) and an amount of an anorectic agent, such thattogether they give effective relief.

In an alternative embodiment of the present invention there is providedthe use of a compound of formula (I) and an anorectic agent for themanufacture of a medicament for reducing the total body fat mass in anobese mammal, especially a human.

The present invention also provides a method for reducing the total bodyfat mass in an obese mammal, especially a human, which method comprisesadministration to a patient in need of such treatment an amount of acompound of formula (I) and an amount of an anorectic agent, such thattogether they give effective relief.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, aminorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfentluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof.

Particularly preferred anorectic agents include amphetamine andderivatives thereof such as amphetamine, benzphetamine,chlorphentermine, clobenzorex, cloforex, clotermine, dexfenfluramine,dextroamphetamine, diethylpropion, N-ethylamphetamine, fenfluramine,fenproporex, furfurylmethylamphetamine, levamfetamine, mefenorex,metamfepramone, methamphetamine, norpseudoephedrine, pentorex,phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine,piclorex and sibutramine; and pharmaceutically acceptable salts thereof.

A particularly suitable class of anorectic agent are the halogenatedamphetamine derivatives, including chlorphentermine, cloforex,clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;and pharmaceutically acceptable salts thereof;

Particularly preferred halogenated amphetamine derivatives of use incombination with a compound of the present invention include:fenfluramine and dexfenfluramine, and pharmaceutically acceptable saltsthereof.

It will be appreciated that for the treatment of prevention of obesity,the compounds of the present invention may also be used in combinationwith a selective serotonin reuptake inhibitor (SSRI).

The present invention accordingly provides the use of a compound offormula (I) and an SSRI for the manufacture of a medicament for thetreatment or prevention of obesity.

The present invention also provides a method for the treatment orprevention of obesity, which method comprises administration to apatient in need of such treatment an amount of a compound of formula (I)and an amount of an SSRI, such that together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition for the treatment or prevention of obesitycomprising a compound of formula (I) and an SSRI, together with at leastone pharmaceutically acceptable carrier or excipient.

It will be appreciated that the compound of formula (I) and SSRI may bepresent as a combined preparation for simultaneous, separate orsequential use for the treatment or prevention of obesity. Such combinedpreparations may be, for example, in the form of a twin pack.

In a further or alternative aspect of the present invention, there istherefore provided a product comprising a compound of formula (I) and anSSRI as a combined preparation for simultaneous, separate or sequentialuse in the treatment or prevention of obesity.

In an alternative embodiment of the present invention, there is providedthe use of a compound of formula (I) and an SSRI for the manufacture ofa medicament for reducing the total body fat mass in an obese mammal,especially a human.

The present invention also provides a method for reducing the total bodyfat mass in an obese mammal, especially a human, which method comprisesadministration to the mammal an amount of a compound of formula (I) andan amount of an SSRI, such that together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition for reducing the total body fat mass in anobese mammal, especially a human, comprising a compound of formula (I)and an SSRI, together with at least one pharmaceutically acceptablecarrier or excipient.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

As used herein "obesity" refers to a condition whereby a mammal has aBody Mass Index (BMI), which is calculated as weight per height squared(kg/m²), of at least 25.9. Conventionally, those persons with normalweight, have a BMI of 19.9 to less than 25.9.

The obesity herein may be due to any cause, whether genetic orenvironmental. Examples of disorders that may result in obesity or bethe cause of obesity include overeating and bulimia, polycystic ovariandisease, craniopharyngioma, the Prader-Willi Syndrom, Frochlich'ssyndrom, Type II diabetes, GH-deficient subjects, normal variant shortstature, Turner's syndrom, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia.

"Treatment" (of obesity) refers to reducing the BMI of the mammal toless than about 25.9, and maintaining that weight for at least 6 months.The treatment suitably results in a reduction in food or calorie intakeby the mammal.

"Prevention" (of obesity) refers to preventing obesity from occurring ifthe treatment is administered prior to the onset of the obese condition.Moreover, if treatment is commenced in already obese subjects, suchtreatment is expected to prevent, or to prevent the progression of, themedical sequelae of obesity, such as, e.g., arteriosclerosis, Type IIdiabetes, polycycstic ovarian disease, cardiovascular diseases,osteoarthritis, dermatological disorders, hypertension, insulinresistance, hypercholesterolemia, hypertriglyceridemia, andcholelithiasis.

Thus, in one aspect, this invention relates to the inhibition and/orcomplete suppression of lipogenesis in obese mammals, i.e., theexcessive accumulation of lipids in fat cells, which is one of the majorfeatures of human and animal obesity, as well as loss of total bodyweight. In another aspect, the invention ameliorates the conditions thatare a consequence of the disease, such as preventing or arresting theprogression of polycystic ovarian disease so that the patient is nolonger infertile, and increasing the insulin sensitivity and/ordecreasing or eliminating the need or usage of insulin in a diabeticpatient, e.g., one with adult-onset diabetes or Type II diabetes.

A further aspect of the present invention comprises the use of acompound of formula (I) for achieving a chronobiologic (circadian rhythmphase-shifting) effect and alleviating circadian rhythm disorders in amammal. The present invention is further directed to the use of acompound of formula (I) for blocking the phase-shifting effects of lightin a mammal.

The present invention further relates to the use of a compound offormula (I) for enhancing or improving sleep quality, in particular byincreasing sleep efficiency and augmenting sleep maintenance, as well asfor preventing and treating sleep disorders and sleep disturbances, in amammal.

In a preferred embodiment, the present invention provides a method forthe phase advance or phase delay in the circadian rhythm of a subjectwhich comprises administering to the subject an appropriate amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

"Mammals" include animals of economic importance such as bovine, ovine,and procine animals, especially those that produce meat, as well asdomestic animals, sports animals, zoo animals, and humans, the latterbeing preferred.

It will be appreciated that when using any combination described herein,both the compound of formula (I) and the other active agent(s) will beadministered to a patient, within a reasonable period of time. Thecompounds may be in the same pharmaceutically acceptable carrier andtherefore administered simultaneously. They may be in separatepharmaceutical carriers such as conventional oral dosage forms which aretaken simultaneously. The term "combination" also refers to the casewhere the compounds are provided in separate dosage forms and areadministered sequentially. Therefore, by way of example, one activecomponent may be administered as a tablet and then, within a reasonableperiod of time, the second active component may be administered eitheras an oral dosage form such as a tablet or a fast-dissolving oral dosageform. By a "fast dissolving oral formulation" is meant, an oral deliveryform which when placed on the tongue of a patient, dissolves withinabout 10 seconds.

By "reasonable period of time" is meant a time period that is not inexcess of about 1 hour. That is, for example, if the first activecomponent is provided as a tablet, then within one hour, the secondactive component should be administered, either in the same type ofdosage form, or another dosage form which provides effective delivery ofthe medicament.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regiment of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis using an injectable formulation, a suitabledosage level is about 0.001 to 10 mkg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the mature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

According to a general process (A.1), the compounds according to theinvention in which X is --CH₂ -- and Y is --CH₂ -- or --CH₂ CH₂ -- maybe prepared by the reduction of a compound of formula (I) in which thebroken line represents a double bond, herein after referred to as acompound of formula (IIA) ##STR11## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹,R¹⁰, p and q are as defined in relation to formula (I) and Y' is --CH═or --CH₂ CH═.

Suitable reducing conditions include: catalytic hydrogenation using ametal catalyst such as palladium or platinum or hydroxides or oxidesthereof, preferably in a suitable solvent such as alcohol, e.g. methanolor ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g.acetic acid, or a mixture thereof; or using trifluoroacetic acid andtriethylsilane.

Similarly, according to a general process (A.2), compounds of formula(I) wherein X is --CH₂ -- and Y is --CH₂ -- or --CH₂ CH₂ --, may beprepared by the reduction of a compound of formula (IIB) ##STR12##wherein Y" is --CH₂ -- or --CH₂ CH₂ --, using the reaction conditionsdescribed in process (A.1), above.

According to another general process (B), compounds of formula (I), inwhich X is --CH₂ -- and Y is --CH═ or --CH₂ CH═ and the broken line is adouble bond (i.e. compounds of formula (II)), may be prepared by thereaction of a compound of formula (III) ##STR13## wherein R⁴, R⁵, R⁶,R⁹, R¹⁰ and q are as defined in formula (I), Y' is --CH═ or --CH₂ CH═and each R⁴⁵ is a C₁₋₄ alkyl group, preferably methyl or butyl groups,with a compound of formula (IV) ##STR14## wherein R¹, R², R³ and p areas defined in formula (I) and Hal is a halogen atom, for example,chlorine, bromine or iodine, especially bromine.

The reaction is conveniently effected in the presence of lithiumchloride and a transition metal catalyst such astetrakis(triphenylphosphine) palladium (0). Suitable solvents for thereaction include aromatic hydrocarbons, for example, toluene, thereaction being effected at a temperature between 80° C. and the refluxtemperature of the solvent.

According to another general process (C), compounds of formula (I) maybe prepared by the interconversion of a corresponding compound offormula (I) in which R⁶ is H, hereinafter referred to as a compound offormula (V) ##STR15## wherein R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰, X, Y, p, qand the broken line are as defined in relation to formula (I) byreaction with a compound of formula (VI):

    LG--R.sup.6a                                               (VI)

where R^(6a) is a group of the formula R⁶ as defined in relation toformula (I) or a precursor therefor and LG is a leaving group such as aalkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or ahalogen atom (e.g. bromine, chlorine or iodine); and, R^(6a) is aprecursor group, converting it to a group R⁶ (in which process anyreactive group may be protected and thereafter deprotected if desired).

This reaction may be performed in conventional manner, for example in anorganic solvent such as dimethylformamide in the presence of an acidacceptor such as potassium carbonate.

According to a further process (D), compounds of formula (I) may beprepared by further interconversion processes from other compounds offormula (I) using suitable procedures. In particular, processes may beused to vary the group R⁶. For example, compounds of formula (I) whereinR⁶ is other than H may be prepared from the corresponding compounds offormula (I) wherein R⁶ is H by reaction with a reagent suitable tointroduce the group R⁶, for example, compounds of formula (I) wherein R⁶is COR^(a) may be prepared form compounds of formula (I) wherein R⁶ is Hby, for example, reaction with an appropriate acid anhydride.

Compounds of formula (I) wherein R⁶ is C₁₋₆ alkyl may be prepared fromcorresponding compounds of formula (I) wherein R⁶ is COR^(a) byreduction using, for example, borane or a borohydride such as sodiumcyanoborohydride.

Compounds of formula (I) wherein R⁶ is C₁₋₆ alkyl substituted byCONR^(a) R^(b) may be prepared from corresponding compounds of formula(I) wherein R⁶ is C₁₋₆ alkyl substituted by CO₂ R^(a) by treatment withammonia or an amine of formula NR^(a) R^(b).

According to another general process (E), compounds of formula (I)wherein p is zero and R³ is a tetrazol-1-yl group may be prepared byreaction of intermediates of formula (VII) ##STR16## with ammoniumchloride and sodium azide at elevated temperature, conveniently in asolvent such as dimethylformamide.

According to another general process (F), compounds of formula (I) maybe prepared by a coupling reaction between a compound of formula (VIII)and (IX) ##STR17## wherein one of R⁴⁰ and R⁴¹ is B(OH)₂ or Sn(alkyl)₃ ora derivative thereof, and the other is a leaving group such as a halogenatom e.g. bromine or iodine, or --OSO₂ CF₃. Where one of R⁴⁰ and R⁴¹ isB(OH)₂, the reaction is conveniently effected in the presence of apalladium (0) catalyst such as tetrakis(triphenylphosphine)palladium (0)in a suitable solvent such as an ether, for example, dimethoxyethane atan elevated temperature. Where one of R⁴⁰ and R⁴¹ is Sn(alkyl)₃, thereaction is conveniently effected in the presence of palladium (II)catalyst such as bis(triphenylphosphine) palladium (II) chloride, in asuitable solvent such as an aromatic hydrocarbon, for example, toluene,at an elevated temperature.

According to another general process (G), compounds of formula (I) maybe prepared from a compound of formula (X) ##STR18## wherein Y" is --CH₂-- or --CH₂ CH₂ --, by an acid catalysed intramolecular cyclisationreaction.

Suitable acids of use in the reaction include mineral acids such ashydrochloric acid. The reaction is conveniently effected in a suitableorganic solvent, such as an alcohol, e.g. methanol, at an elevatedtemperature, for example, at the reflux temperature of the chosensolvent.

According to another general process (H), compounds of formula (I) inwhich X is --CH₂ -- and Y is --CH₂ -- or --CH₂ CH₂ --, may be preparedform a compound of formula (XX) ##STR19## by reaction with a compound offormula (IV) wherein Hal in formula (IV) is chlorine, bromine or,preferably, iodine, under the conditions of a reductive Heck reactionusing a palladium catalyst such as palladium acetate with, for example,tri-o-tolyphosphine, dimethylformamide and tributylamine, and a reducingagent, preferably formic acid or a salt thereof, such as potassiumformate.

According to another general process (J), compounds of formula (I) inwhich X is --CH₂ -- and Y is --CH═ or --CH₂ CH═ (i.e. a compound offormula (IIA), above) may be prepared by the dehydration of a compoundof formula (XXI) ##STR20## wherein Y" represents --CH₂ -- or --CH₂ CH₂--, using an acid such as trifluoroacetic acid. The reaction isconveniently effected at a temperature between 0° C. and roomtemperature, using a suitable organic solvent such as dichloromethane.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (IIB) may be prepared using the method of generalprocess (J) described above.

Intermediates of formula (V) may be prepared in a similar manner to themethods of processes (A), (B), (E), (F),(G), (H) and (J), preferablywith an amino protecting group on the piperdine nitrogen atom. Suitableamino protecting groups include alkoxycarbonyl groups such astert-butoxycarbonyl and trichloroethoxycarbonyl, aralkyloxycarbnylgroups such as benzyloxycaronyl, or aralkyl groups such as benzyl.Removal of the protecting group is effected by conventional proceduresthus, for example, tert-butoxycarbonyl groups may be removed underacidic conditions using, for example, trifluoroacetic acid;tert-butoxycarbonyl groups, together with benzyloxycarobnyl and benzylgroups, may also be removed be hydrogenolysis in the presence of acatalyst, for example, palladium; and trichloroethoxycarbonyl groups maybe removed with zinc dust.

Intermediates of formula (III) may be prepared from a compound offormula (XI) ##STR21## wherein R⁵⁰ is a triflate (--OSO₂ CF₃) group or abromine or iodine atom, by reaction with a compound of the formula(R⁴⁵)₃ Sn--Sn(R⁴⁵)₃, for example, hexamethyl distannane. The reaction isconveniently effected in the presence of a base, for example, lethiumcarbonate, and a catalyst such as triphenylphosphine palladium(0).Suitable solvents for the reaction include ethers such astetrahydrofuran, the reaction being effected at a temperature betweenroom temperature and 100° C., for example, at about 60° C.

Compounds of formula (XI) may be prepared from a compound of formula(XII): ##STR22## by enolisation of the ketone in the presence of a base,for example, sodium hexamethyldisilazide, followed by reaction with areagent capable of introducing a suitable leaving group, for instance,where R⁵⁰ is --OSO₂ CF₃, using2-[N,N-bis(trifluoromethylsulphonyl)amino]-5-chloropyridine or triflicanhydride. The reaction is conveniently effected in a suitable solventsuch as an ether, for example, tetrahydrofuran at a reduced temperature,for instance, -80° C.

Compounds of formula (XII) may be prepared from a compound of formula(XIII) by the following reaction sequences (Scheme A or Scheme B) or bymethods analogous thereto (with the proviso that R⁹ and R¹⁰ are notoxo): ##STR23##

In a preferred embodiment of the aforementioned processes, R⁶ isreplaced with an amino protecting group, in particulartert-butoxycarbonyl which is conveniently removed prior to reduction ofthe 7-aza-spiro[4.5]dec-3-ene structure (general process (A)).

Compounds of formula (III), wherein Y' is --CH═, may also be preparedfrom a compound of formula (XIII) by the following reaction sequence(Scheme C) or by methods analogous thereto: ##STR24##

In another preferred embodiment of the aforementioned processes, R⁶ is abenzyl group. The reduction reaction described as process (A) above forthe preparation of compounds of formula (I) may conveniently replace thebenzyl group with a hydrogen atom (i.e. forming a compound of formula(V)).

Compounds of formula (IV) in which p is zero may be prepared byconventional methodology, for example, from a compound of formula (XIV)##STR25## by reaction with a suitable anhydride of the formula (RCO)₂ O,where R is the desired substituent for the tetrazole 5-position,followed by reaction with triphenylphosphine in carbon tetrachloride,followed by the further step of (i) reaction with an azide such assodium azide to effect the formation of the tetrazole ring; or (ii)reaction with hydrazine hydrate to effect the formation of a1,2,4-triazole ring; or (iii) reaction with aminoacetaldehyde diethylacetal to effect the formation of an imidazolyl ring.

Compounds of formula (XIV) may be prepared from the corresponding nitrocompound by reduction using, for example, iron powder, or Raney nickelin a conventional manner.

The compounds of formula (XIV) or their nitro precursors are eitherknown compounds or may be prepared using conventional methodology.

Compounds of formula (VII) may be prepared by reaction of a compound offormula (III) with a compound of formula (XV) ##STR26## according to themethods described above, followed by reduction according to the methodof general process (B).

Intermediates of formula (X) wherein Y" is --CH₂ CH₂ -- may be preparedby the reduction of a compound of formula (XVI) ##STR27## or a protectedderivative thereof, using conventional methodology, for instance, bycatalytic hydrogenation using a metal catalyst such as palladium orplatinum or oxides thereof, preferably in a solvent such as an alcohol,e.g. ethanol, or an ester, e.g. ethyl acetate.

Compounds of formula (XVI) may be prepared by the reaction of a compoundof formula (XIII) with a compound of formulae (XVII) ##STR28## or aprotected derivative thereof, by lithiation using n-butyl lithiumfollowed by quenching with, for example, sodium dihydrogenorthophosphate. The reaction is conveniently effected in a solvent suchas an ether, e.g. tetrahydrofuran, at a reduced temeprature, forexample, at -78° C.

Alternatively, compounds of formula (X) may be prepared by the reactionof a compound of formula (XIII) with a Grignard reagent of formula(XXII) ##STR29## wherein R⁵⁰ is a suitable hydroxy protecting group,preferably benzyl, and Hal is a halogen atom, preferably chlorine,followed by removal of the protecting group R⁵⁰. Utilisation of a chiralintermediate of formula (XXII) is particularly suitable for controllingthe stereochemistry of the 3-position in compounds of formula (I).

Compounds of formula (XXII) may be prepared by conventional methods wellknown in the art.

In a further alternative method, compounds of formula (X) may beprepared by the reduction of a compound of formula (XXIII) ##STR30##using, for example, catalytic hydrogenation in the presence of a metalcatalyst such as palladium or platinum or hydroxides or oxides thereof,pregerably in a suitable solvent such as an alcohol, e.g. methanol, anester, e.g. ethyl acetate, or an organic acid, e.g. acetic acid, or amixture thereof.

Compounds of formula (XXIII) in which Y' is --CH═, may be prepared froma compound of formula (XXIV) ##STR31## by reaction with a compound offormula (IV) using reductive Heck conditions as described in generalprocess (H), above.

Compounds of formula (XXIV) may be prepared from compounds of formula(XIII) and, for example, a Grignard reagent prepared fromO-trimethylsilylpropargyl alcohol using conventional methodology,followed by removal of the hydroxy protecting group.

According to another method, compounds of formula (X) in which X is--CH₂ --, may be prepared from a compound of formula (XXV) ##STR32## byreaction with borane in tetrahydrofuran, followed by an oxidativework-up using, for example, hydrogen peroxide and sodium hydroxide.

Compounds of formula (XXV) may be prepared from a compound of formula(XIII) and, for example, a Grignard reagent prepared from a2-aryl-3-bromo-1-propene using conventional methodology.

Compounds of formula (XXI) may be prepared by the reaction of a compoundof formula (XII) with Grignard reagent prepared from a compound offormula (IV), preferably using magnesium and a bromide of formula (IV).The coupling reaction is conveniently effected at reduced temperature,for example at about 0° C., using a suitable solvent such as an ether,for example, diethyl ether.

Compounds of formula (XX) may be prepared, for example, by theconversion of a stannane of formula (III) to the corresponding iodide bytreatment with iodine at reduced temperature, for example, at about -78°C., in a suitable solvent such as dichloromethane. The iodine may thenbe displaced to give the compound of formula (XX) by treatment with, forexample, α,α'-azo-isobutyronitrile and tributyltin hydride in a suitablesolvent, for example, toluene, at an elevated temperature, for example,at about 100° C.

Alternatively, compounds of formula (XX) may be prepared by thecyclisation of a compound of formula (XXVI) ##STR33## using thedehydrating conditions described above for general process (J) or usingtriphenylphosphine and diethylazodicarboxylate in a suitable solventsuch as tetrahydrofuran.

Compounds of formula (XXVI) may be prepared by the partial reduction ofan acetylene compound of formula (XXIV). The reaction is convenientlyeffected by catalytic hydrogenation using a metal catalyst such aspalladium on calcium carbonate in the presence of a lead poison (e.g.Lindlar catalyst). Other suitable methods will be readily apparent to aperson of ordinary skill in the art.

Compounds of formula (XIII) may be prepared by methods described inEuropean Patent Specification No. 0 577 394-A, or by analogous methods.

Compounds of formula (XVII) are known compounds (see Chemische Berichte,(1088) 121, 1315-1320) or may be prepared by methods analogous to thosedescribed therein.

Compounds of formula (IX) and (XV) are known compounds or may beprepared by conventional methods or using techniques analogous to thosetaught herein.

Further useful methodology for the preparation of compounds in which R⁶contains a heterocyclic group is described, for example, inInternational Patent Specification No. WO 95/18124.

It will be appreciated that compounds of the formula (I) wherein R⁶contains an ═O or ═S substituent can exist in tautomeric forms. All suchtautomeric forms and mixtures thereof are included within thisinvention. Most aptly the ═O or ═S substituent in R⁶ is the ═Osubstituent.

Where they are not commercially available, the intermediates of formula(VI) above may be prepared by the procedures described in theaccompnying Examples or by alternative procedures which will be readilyapparent to one skilled in the art.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds were found to be active with IC₅₀ at the NK₁receptor of less than 1 μM on said test method.

For the avoidance of doubt, the nomenclature adhered to throughout thisspecification follows the general principle illustrated below: ##STR34##

The following non-limiting Examples serve to illustrate the preparationof compounds of the present invention:

DESCRIPTION 1 (2S)-1-tert-Butoxycarbonyl-2-phenylpiperidin-3-one

To a cooled (-60° C.) solution of oxalyl chloride (0.68 ml, 7.8 mmol) indichloromethane (17 ml) was added dimethyl sulfoxide (0.69 ml, 9.8 mmol)over 10 minutes before addition of(2S,3S)1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared bythe method described in European Patent Specification number 0 528495-A) in dichloromethane (7 ml). The solution was stirred at -60° C.for 20 minutes, warmed to -30° C. and triethylamine (2.5 ml) added. Thesolution was warmed to 0° C. then was washed with ice cold 10% aqueouscitric acid solution (40 ml, twice) water and dried (MgSO₄). Thesolution was evaporated to dryness to give the title compound and thiswas used immediately without further purification. ¹ H NMR (250 MHz,CDCl₃) δ 7.5-7.3 (5H,m), 5.8 (1H, bs), 4.2 (1H, bs), 3.4 (1H, m), 2.6(2H, m), 2.0 (2H, m), 1.54 (9H, s).

DESCRIPTION 2(2S,3R)-1-tert-Butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine

A tetrahydrofuran solution of3-(chloromagnesio)-2-(phenoxymethyl)-1-propene (0.91 M, 3 ml) (Louw et.al. Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 mmol of3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of(2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc.1) in THF (3ml). The solution was stirred at room temperature for 1 hour, quenchedby addition of saturated ammonium chloride solution (20 ml) andextracted with ethyl acetate (20 ml). The organic phase was washed(saturated brine), dried (MgSO₄), evaporated to a small volume andpurified by chromatography on silica gel eluting with hexane containingincreasing proportions of ethyl acetate between 0% to 20%. Evaporationof the fractions gave(2S,3R)-1-tert-butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine.MS (ES⁺) m/z 424 (M+H), 324 (M+2H-^(t) BuOCO--), 368 (M+2H-^(t) Bu). ¹ HNMR (360 MHz, CDCl₃) δ 7.48 (2H, d, J 6.9 Hz), 7.35-7.2 (6H, m) 6.9-6.88(3H, m), 5.4 (1H, s), 5.15 (2H, d, J 13.7 Hz), 4.61 (2H, s), 4.11 (2H,m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J 14.0 Hz), 1.95 (2H, m),1.79 (2H, m), 1.36 (9H, s).

DESCRIPTION 3(6S,5R)-3-Methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane

To a cooled (-80° C.) solution of(2S,3R)1-tert-butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine(1.53 g, 3.62 mmol; Desc.2) in THF (20 ml) was added a solutionn-butyllithium in hexanes (2.5 M, 1.45 ml, 3.62 mmol) followed by asolution of zinc chloride (0.5 M in THF, 7.24 ml, 3.62 mmol). Thesolution was allowed to warm to room temperature, triphenylphosphinepalladium (0) (0.23 g, 0.2 mmol) added, degassed and then heated toreflux for 16 hours. After removal of the solvent by evaporation theresidue was partitioned between ethyl acetate and 2 M NaOH. The organicphase was washed with saturated brine, dried (MgSO₄) and purified bychromatography on silica gel eluting with hexane containing increasingproportions of ethyl acetate between 0% to 5%. Evaporation of thefractions gave(6S,5R)-3-methylene-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane.¹ H NMR (360 MHz, CDCl₃) δ 7.58 (2H, d, J 8.4 Hz), 7.32-7.21 (3H, m),5.23 (1H, s), 5.06 (1H, m), 4.97 (1H, m), 4.39 (2H, AB d, J 13.3 Hz),3.99 (1H, dd, J 13.3, 4.48 Hz), 2.83 (1H, ABd J 15.5 Hz), 2.7 (1H,td J12.5 Hz 3.93 Hz) 2.5 (1H, ABd, J 15.4 Hz), 2.15 (2H, td, J 12.3 Hz 4.4Hz), 1.69 (2H, m), 1.46 (9H, s). MS (ES⁺) m/z 329 (M+2H-^(t) BuOCO).

DESCRIPTION 4(6S,5R)-7-(tert-Butoxycarbonyl)-3-keto-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

Through a cooled (-80° C.) solution of(6S,5R)-7-(tert-butoxycarbonyl)-3-methylene-6-phenyl-7-aza-1-oxa-spiro[4.5]decane(0.665 g; Desc.3) in dichloromethane (5 ml) and methanol (5 ml) wasbubbled a mixture of ozone and oxygen for 0.75 hours. After the solutionhad been purged with nitrogen, dimethyl sulphide (0.5 ml) was added andthen stirred under nitrogen at room temperature for 16 hours. Thesolvent was removed in vacuo and the residue partitioned between ethylacetate and water. The organic phase was dried (MgSO₄), evaporated andthe residue purified by chromatography on silica gel elutintg withhexane containing increasing proportions of ethyl acetate between 0% to10%. Evaporation of the fractions gave the title compound. MS (ES⁺) m/z332 (M+H), 232 (M+2H-^(t) BuOCO--), 276 (M+2H-^(t) Bu). ¹ H NMR (250MHz, CDCl₃) δ 7.58 (2H, d, J 6.2 Hz), 7.37-7.26 (3H, m), 5.3 (1H, s),4.15 and 4.09 (2H, AB d, J 17.4 Hz), 3.97 (1H, m), 2.80 (1H, td, J 12.9Hz and 4.0 Hz), 2.74 and 2.48 (2H, ABd, J 18.1 Hz), 2.29 (2H, m),1.88-1.63 (2H, m), 1.44 (9H, s).

DESCRIPTION 5(6S,5R)-7-(tert-Butoxycarbonyl)-3-(trifluoromethylsulfonyloxy)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

To a cooled (-80° C.) solution of 1 M sodium hexamethyldisilazide (0.38ml, 0.38 mmol) in THF was added a solution of(6S,5R)-7-(tert-butoxycarbonyl)-3-keto-6-phenyl-7-aza-1-oxa-spiro[4.5]decane(0.105 mg, 0.319 mmol; Desc.4) in THF (3 ml). The solution was stirredfor 1 hour at -80° C. and a solution of2-[N,N-bis(trifluoromethylsulphonyl)amino]-5-chloropyridine (0.163 g,0.415 mmol) in THF (3 ml) was added. The solution was stirred at -80° C.for 30 minutes then at room temperature for 30 minutes before beingquenched by addition of sat. aq. ammonium chloride solution and ethylacetate. The dried (MgSO₄) organic phase was purified by chromatographyon silica gel eluting with hexane containing increasing proportions ofethyl acetate between 0% to 5%. Evaporation of the fractions gave thetitle compound. MS (ES⁺) m/z 464 (M+H), 364 (M+2H-^(t) BuOCO--), 408(M+2H-^(t) Bu). ¹ H NMR (360 MHz, CDCl₃) δ 7.4 (2H, d, J 7.3 Hz),7.3-7.22 (3H, m), 6.01 (1H, t, J 2.13 Hz), 5.13 (1H, s) 4.56 and 4.26(2H, ABdd, J 12.4 Hz and 1.97 Hz), 4.10 (1H, dt, J 12.6 Hz and 4.22 Hz),3.00 (1H, m), 2.28-2.04 (2H, m) 1,.88-1.76 (2H, m), 1.37 (9H, s).

DESCRIPTION 6(6S,5R)-7-(tert-Butoxycarbonyl)-6-phenyl-3-(trimethylstannyl)-7-aza-1-oxa-spiro[4.5]dec-3-ene

To a degassed solution of(6S,5R)-7-(tert-butoxycarbonyl)-6-phenyl-3-(trifluoromethylsulphonyloxy)-7-aza-1-oxa-spiro[4.5]dec-3-ene(0.482 g, 1.04 mmol; Desc.5), lithium chloride (0.264 g, 6.25 mmol),lithium carbonate (0.076 g) and hexamethyl distannane (0.96 g, 2.9 mmol)in THF (10 ml) was added triphenylphosphine palladium (0) (0.06 g). Thesolution was degassed and then heated at 60° C. for 5 hours undernitrogen. Water (20 ml) and ethyl acetate (20 ml) were added and thedried organic phase was purified by chromatography on silica gel(eluting with hexane containing increasing proportions of ethyl acetatebetween 0% to 5%. Evaporation of the fractions gave the title compoundas a crystalline solid. ¹ H NMR (360 MHz, CDCl₃) δ 7.25 (2H, d, J 7.3Hz), 7.1-7.0 (3H, m), 5.83 (1H, t, J 2.5 Hz), 4.78 (1H, s), 4.48 and4.02 (2H, dd, J 12.9 Hz and 2.3 Hz), 3.96 (1H, dd, J 6.16 Hz and 13.4Hz), 2.95 (1H, td, J 13.3 Hz and 4.5 Hz), 1.84 (1H, m), 1.68 (1H, m),1.60 (2H, m), 1.19 (9H, s), 0 (6H, s).

DESCRIPTION 7 3-Bromo-4-(5-(trifluoromethyl)tetrazol-1-yl)anisole

a) 2-Bromo-4-methoxyaniline

To a solution of p-anisidine (10 g, 0.08 mol) and sodium carbonate (17.2g, 0.16 mol) in dichloromethane (400 ml) was added a solution of bromine(3.8 ml), 0.072 mol) in dichloromethane (200 ml) dropwise. The reactionwas stirred at ambient temperature for 45 minutes, diluted withdichloromethane (200 ml) and washed with water (2×200 ml). The organiclayer was dried over magnesium sulphate, and the solvent was removed invacuo to yield a dark brown oil. Chromatography on silica eluting with agradient of ethyl acetate in hexane (10%, 15% and 20%) afforded thetitle compound as a dark red oil (4 g, 25%), m/z (ES⁺) 202 (M³⁰ +H,100%). ¹ H NMR (250 MHz, CDCl₃) δ 3.73 (3H, s), 3.78 (2H, broad s), 6.72(2H, t, J 1.2 Hz), 7.00 (1H, q, J 1.26 Hz).

b) 3-Bromo-4-(trifluoroacetamido)anisole

2-Bromo-4-methoxyaniline (4 g, 0.02 mol) was dissolved indichloromethane (30 ml) containing triethylamine (2.77 ml, 0.02 mol).The solution was cooled to -10° C. and trifluoroacetic anhydride (2.81ml, 0.02 mol) was added slowly. The reaction was stirred at ambienttemperature for 15 minutes, diluted with dichloromethane (50 ml) andwashed with water (2×50 ml). The organic layer was dried over magnesiumsulphate and the solvent was removed in vacuo. Chromatography on silicaeluting with 10-15% ethyl acetate in hexane afforded the title compoundas an orange solid (4.7 g, 79%). ¹ H NMR (360 MHz, CDCl₃) δ 3.81 (3H,s), 6.92 (1H, dd, J 2.8 Hz, J 9.1 Hz), 7.15 (1H, d, J 2.8 Hz), 8.14 (1H,d, J 9.1 Hz), 8.23 (1H, broad s).

c) 3-Bromo-4-(5-(trifluoromethyl)tetrazol-1-yl)anisole

3-Bromo-4-(trifluoroacetamido)anisole (4.7 g, 0.16 mol) was suspended incarbon tetrachloride (60 ml) and triphenylphosphine (6.2 g, 0.024 mol)was added. The reaction was heated at reflux for 12 hours. The reactionwas allowed to cool to ambient temperature, and filtered. The solid waswashed thoroughly with ethyl acetate:diethyl ether (1:1, 200 ml:200 ml).The filtrate was concentrated in vacuo to afford a red solid. This solidwas dissolved in N,N-dimethylformamide (10 ml) and this solution wasadded to sodium azide (1.55 g, 0.024 mol). The reaction was stirred atambient temperature for 12 hours, and diluted with water (100 ml). Theproduct was extracted into ethyl acetate (3×50 ml) and the combinedorganics were washed with brine (100 ml), dried over magnesium sulphateand the solvent removed in vacuo. Chromatography on silica eluting with10% ethyl acetate in hexane afforded the title compound as a pale orangesolid (4.2 g, 66%), m/z (ES⁺) 323 (M⁺ +H, 100%). ¹ H NMR (250 MHz,CDCl₃) δ 3.92 (3H, s), 7.03 (1H, dd J 2.7 Hz, J 8.8 Hz), 7.30 (1H, d, J2.7 Hz), 7.34 (1H, d, J 8.8 Hz).

DESCRIPTION 8(5R,6S)-7-(tert-butoxycarbonyl)-3-(5-methoxy-2-(5-(trifluoromethyl)-tetrazol-1-yl)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

A mixture of(5R,6S)-7-(tert-butoxycarbonyl)-6-phenyl-3-(trimethylstannyl)-7-aza-1-oxa-spiro[4.5]dec-3-ene(0.5 g, 1 mmol; Desc.6), lithium chloride (0.266 g, 6 mmol) and3-bromo-4-(5-(trifluoromethyl)-tetrazol-1-yl)anisole (0.404 g, 1.2 mmol;Desc. 7c) in toluene (15 ml) was degassed and purged with nitrogenbefore addition of tetrakis(triphenylphosphine)palladium(0) (0.06 g).The mixture was degassed thoroughly, and the solution was heated to 110°C. for 19 hours. The solvent was evaporated in vacuo. The residue wasdry loaded onto silica from methanol, and purified by chromatography onsilica eluting with 10-20% ethyl acetate in hexane, to afford the titlecompound as a yellow oil (500 mg, 90%) MS (CI⁺) m/z 558 (M+H, 60%). ¹ HNMR (250 MHz, CDCl₃) δ 1.34 (9H, s), 1.50 (1H, m), 1.55 (1H, m), 1.67(1H, m), 1.87 (1H, m), 3.08 (1H, m), 3.88 (3H, s), 4.02 (1H, m), 4.30(1H, dd, J 2.1 Hz, J 12.4 Hz), 4.46 (1H, dd, J 2.1 Hz, J 12.4 Hz), 4.92(1H, s), 5.30 (1H, t, J 0.9 Hz), 6.68 (1H, d, J 2.8 Hz), 6.98 (1H, dd, J2.8 Hz, J 8.8 Hz), 7.25 (6H, m).

DESCRIPTION 9 3-Bromo-4-(tetrazol-1-yl)anisole

2-Bromo-4-methoxyaniline (1.2 g, 6 mmol; Desc. 7a) was dissolved inglacial acetic acid (10 ml) and heated to 75° C. To this solution wasadded triethylorthoformate (2.5 ml, 15 mmol) and heated at 75° C. for 1hour. Sodium azide (1.16 g, 18 mmol) was added portionwise and reactionheated at 75° C. for a further 3 hours and stirred at ambienttemperature for 24 hours. The reaction was diluted with water (100 ml)and product extracted into ethyl acetate (3×70 ml). The combinedorganics were washed with brine (100 ml), dried over magnesium sulphateand the solvent removed in vacuo. Medium pressure chromatography elutingwith 40% ethyl acetate/hexane afforded the title compound as a whitesolid (1.5 g, 90%). ¹ H NMR (360 MHz, d₆ -DMSO) δ 3.88 (3H, s), 7.20(1H, dd, J 2.7 Hz, J 8.8 Hz), 7.51 (1H, d, J 2.7 Hz), 7.68 (1H, d, J 8.8Hz), 9.83 (1H, s).

DESCRIPTION 10(5R,6S)-7-(tert-Butoxycarbonyl)-3-(5-methoxy-2-(tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-spiro[4.5]dec-3-ene

This compound was prepared according to the procedure described inDescription 8. Medium pressure chromatography eluting with 50% ethylacetate/hexane afforded the title compound as a yellow oil (400 mg,78%). ¹ H NMR (360 MHz, CDCl₃) δ 1.32 (9H, s), 1.67 (3H, m), 1.90 (1H,m), 3.11 (1H, m), 3.88 (3H, s), 4.04 (1H, m), 4.09 (1H, dd, J 2.1 Hz, J12.4 Hz), 4.40 (1H, dd, J 2.1 Hz, J 12.4 Hz), 4.90 (1H, s), 5.44 (1H, t,J 2.1 Hz), 6.73 (1H, d, J 2.8 Hz), 6.96 (1H, dd, J 2.9 Hz, J 8.8 Hz),7.25 (5H, m), 7.43 (1H, d, J 8.8 Hz), 8.56 (1H, s).

DESCRIPTION 11(5R,6S)-3-(2-Benzyloxy-5-(trifluoromethyoxy)phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

a) 2-Bromo-4-(trifluoromethyoxy)phenyl

To a cooled (0° C.) solution of 4-(trifluoromethoxy)phenol (35.6 g, 0.2mol) in chloroform (280 ml) was added dropwise a solution of bromine (32g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 0° C. for1 hour and at room temperature for 2 hours. Dichloromethane (200 ml) andwater (400 ml) were added and the organic phase was washed further withwater (400 ml), brine (200 ml) and dried (MgSO₄). The solvent wasremoved and the residue was purified by distillation at reduced pressureto give the title compound. ¹ H NMR (250 MHz, CDCl₃) δ 7.38 (1H, d, J2.1 Hz), 7.13 (1H, dd, J 9.1, 2.1 Hz), 7.03 (1H, d, J 9.1 Hz), and 5.53(1H, s).

b) 2-Benzyloxy-5-(trifluoromethoxy)bromobenzene

2-Bromo-4-(trifluoromethoxy)phenyl (Description 11a; 5 g, 20 mmol) wasdissolved in N,N-dimethylformamide (60 ml), and potassium carbonate (5.4g, 40 mmol) was added, followed by benzyl bromide (3.5 ml, 30 mmol), andthe reaction was stirred at ambient temperature for 15 hours. Thereaction was diluted with water (150 ml) and extracted into ethylacetate (3×60 ml). The combined organic fractions were washed with water(100 ml), brine (100 ml), dried (MgSO₄) and evaporated in vacuo.Purification on silica, eluting with 2% and 5% ethyl acetate in hexanegave the title compound as a clear oil (6.7 g, 96%). ¹ H NMR (250 MHz,CDCl₃) δ 5.47 (2H, s), 7.23 (1H, d, J 9 Hz), 7.43 (1H, dd J 8.2, 2.9Hz), and 7.75 (6H, m).

c)(5R,6S)-3-(2-Benzyloxy-5-(trifluoromethoxy)phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

The compound of Description 6 (5.75 g),2-benzyloxy-5-(trifluromethoxy)bromobenzene (3.97 g) and lithiumchloride (2.39 g) were suspended in toluene (50 ml). The solution waspurged with nitrogen (×3). Tetrakis(triphenylphosphine)palladium(0) (450mg) was added and the solution was purged with nitrogen (×3). Thereaction was heated at 120° C. for 30 hours. The mixture was cooled andfiltered. The filtrate was evaporated to dryness. The residue wasdissolved in acetonitrile (20 ml) and washed with hexane (30 ml). Theproduct was extracted into acetonitrile (3×20 ml). The acetonitrilefractions were combined and methanolic potassium fluoride was added (5%aq., 3 ml). The solution was filtered and the filtrate evaporated todryness. The residue was purified on silica using 10% ethyl acetate inhexane, to yield the title compound as an oil (3.88 g) ¹ H NMR (250 MHz,CDCl₃) δ 1.28 (1H, m), 1.66 (9H, s), 1.69 (1H, m), 2.04 (1H, m), (2.37(1H, m) 3.40 (1H, m), 4.43 (1H, drt, J 12.5, 3.9 Hz), 4.94 (1H, dd, J12.1, 2.1 Hz), 5.25 (1H, dd, J 12.1, 2.02 Hz), 5.62 (3H, m), 6.99 (1H,t, J 2.1 Hz), 7.28 (2H, m), 7.39 (1H, m), 7.57 (5H, m), 7.75 (5H, m).

DESCRIPTION 12(3S,5R,6S)-7-(tert-Butoxycarbonyl)-3-(2-hydroxy-5-(trifluoromethoxy))phenyl-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 11 (3.88 g) was dissolved in ethyl acetate(15 ml) and methanol (15 ml). Palladium hydroxide on carbon (1.00 g) wasadded and the suspension was shaken under a hydrogen atmosphere (50 psi)for 72 hours. The suspension was filtered and the filtrate wasevaporated to dryness. The product was purified by medium pressurechromatography using 25% ethyl acetate in hexane to yield two isomers: A(3R, 5R, 6S epimer; 191 mg) and B (3S, 5R, 6S epimer; 2.3 g). The majorisomer, the title compound, had the following analyses: ¹ H NMR (250MHz, CDCl₃), δ 1.35 (9H, s), 1.74 (3H, m), 2.18 (2H, m), 2.49 (1H, dd, J13.0 8.9 Hz), 2.81 (1H, m), 3.61 (1H, qn, J 7.0 Hz), 3.93 (2H, m), 4.22(1H, dd, J 9.1, 6.9 Hz), 5.30 (1H, s), 6.76 (1H, d, J 7.23 Hz), 6.93(2H, m), 7.29 (3H, m), 7.56 (2H, d, J 6.7 Hz).

DESCRIPTION 13(3S,5R,6S)-7-(tert-Butoxycarbonyl)-6-phenyl-3-(5-(trifluoromethoxy)-2-(trifluoromethylsulfonyloxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 12 (1.8 g) was dissolved in pyridine (8 ml)and cooled to 0° C. Trifluoromethanesulphonic anhydride (1.25 ml) wasadded dropwise. The reaction was stirred at 0° C. for 16 hours. Thereaction was diluted with aqueous copper (II) sulphate solution and theproduct extracted into ethyl acetate (3×50 ml). The combined ethylacetate fractions were dried (brine, MgSO₄) and evaporated to dryness.The residue was purified by flash chromatography on silica eluting with10% ethyl acetate in hexane to yield the product as a colourless oil. ¹NMR (250 MHz, CDCl₃), δ 1.35 (9H, s), 1.75 (3H, m), 2.11 (2H, m), 2.51(2H, dd, J 13.2, 8.2 Hz), 2.92 (1H, m), 3.63 (1H, q, J 7.9 Hz), 3.72(1H, m), 4.00 (1H, d, J 12.7 Hz), 4.24 (1H, dd, J 8.5, 6.6 Hz), 5.17(1H, s), 7.15 (2H, m), 7.30 (3H, m), 7.53 (2H, d, J 6.9 Hz).

DESCRIPTION 14(3S,5R,6S)-7-(tert-Butoxycarbonyl)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 13 (211 mg), 2-(tributylstannyl)furan (0.16ml), and bis(diphenylphosphino)ferrocene dichloropalladium(II) catalyst(50 mg) were suspended in dioxane (5 ml) and the reaction purged(vac/N₂)(x3) via a firestone valve. The reaction was heated at 110° C.for 16 hours. The solution was filtered to remove the catalyst and thefiltrate evaporated to dryness. The residue was dissolved inacetonitrile and the solution washed with hexane. The product wasextracted into acetonitrile (3×20 ml). Potassium fluoride (5% inmethanol) was added to the combined acetonitrile fractions causing aprecipitate to form. The precipitate was removed by filtration, and thefiltrate evaporated to dryness. The residue was purified by mediumpressure chromatography on silica using 15% ethyl acetate in hexane aseluant to yield the title compound as a yellow oil. MS (ES⁺) m/z 444 (M⁺-100)+1, 100%), 488 (M⁺ -56)+1, 80%). ¹ H NMR (250 MHz, CDCl₃), δ 1.34(9H, s), 1.72 (3H, m), 2.09 (1H, m), 2.19 (1H, m), 2.43 (1H, dd, J 12.9,8.01 Hz), 2.85 (1H, m), 3.72 (1H, q, J 7.8 Hz), 3.82 (1H, m), 3.99 (1H,d, J 12.7 Hz), 4.15 (1H, dd, J 8.4, 6.5 Hz), 5.21 (1H, s), 6.47 (1H, dd,J 3.3, 0.6 Hz), 6.51 (1H, dd, J 3.3, 1.8 Hz), 7.12 (1H, d, J 8.5 Hz),7.3 (4H, m), 7.53 (4H, m).

DESCRIPTION 15(5R,6S)-7-(tert-Butoxycarbonyl)-3-(2-(fur-2-yl)-5-(trifluoromethoxy))phenyl-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

a) 5-(Trifluoromethoxy)-2-(trifluoromethylsulfonyloxy)bromobenzene

2-Bromo-5-(trifluoromethoxy)phenol (10 g) was dissolved in pyridine andthe solution was cooled to 0° C.; trifluoromethanesulfonic anhydride(7.2 ml) was added dropwise and the resulting mixture was stirred andallowed to reach room temperature over 2 hours. The mixture was dilutedwith copper sulfate (aq. 100 ml) and extracted with ethyl acetate (3×20ml). The organic layer was dried (brine, MgSO₄) and concentrated invacuo and the residue was purified by chromatography on silica usinghexane as eluant (13.1 g). ¹ H NMR (250 MHz, CDCl₃), δ 7.24-7.29 (1H,m), 7.40 (1H, d, J 12.7 Hz), 7.58 (1H, d, J 2.8 Hz).

b)(5R,6S)-7-(tert-Butoxycarbonyl)-3-(5-(trifluoromethoxy)-2-(trifluoromethylsulfonyloxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

The stannane (Description 19 below) (1.2 g), the bromobenzene describedin a) above (778 mg) and lithium chloride (252 mg) were suspended intoluene and the mixture was degassed and purged with nitrogen (x5,firestone valve). Tetrakis(triphenylphosphine)palladium(0) (100 mg) wasadded and the mixture was repurged with nitrogen. The reaction mixturewas heated at reflux overnight. The mixture was diluted with water andthe product was extracted with ethyl acetate (3×20 ml). The organiclayer was dried (brine, MgSO₄) and concentrated in vacuo and the residuewas purified by medium pressure chromatography on silica using 10% ethylacetate in hexane as eluant to afford the compound as a clear oil (800mg). ¹ H NMR (360 MHz, CDCl₃), δ 1.35 (9H, s), 1.80-1.95 (3H, m),2.10-2.19 (1H, m), 3.12-3.21 (1H, m), 4.11-4.16 (1H, m), 4.51 (1H, dd, J12.3 2.2 Hz), 4.85 (1H, dd, J 12.2, 2.0 Hz), 5.13 (1H, s), 6.53 (1H, t,J 2.0 Hz), 6.94 (1H, d, J 2.6 Hz), 7.18-7.44 (7H, m).

c)(5R,6R)-7-(tert-Butoxycarbonyl)-3-(2-fur-2-yl-5-(trifluoromethoxy))phenyl-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

The triflate described in b) above (800 mg), 2-furylboronic acid,lithium chloride (327 mg) and sodium carbonate (50 mg in water, 2.5 ml)were suspended in dimethoxyethane (15 ml) and the mixture was degassedand purged with nitrogen (x5, firestone valve).Bis(triphenylphosphine)palladium dichloride (100 mg) was added and themixture was repurged with nitrogen. The reaction mixture was heated atreflux overnight. The mixture wad diluted with water and the product wasextracted with ethyl acetate (3×20 ml). The organic layer was dried(brine, MgSO₄) and concentrated in vacuo and the residue was purified bymedium pressure chromatography on silica using 10% ethyl acetate inhexane as eluant to afford the compound as a clear oil (200 mg). ¹ H NMR(250 MHz, CDCl₃), δ 1.34 (9H, s), 1.61 (3H, br s), 1.80 (2H, m), 2.12(1H, m), 3.19 (1H, s), 4.13 (2H, m), 4.19 (1H, dd, J 12.5, 2.2 Hz), 4.55(1H, dd, J 12.5, 2.0 Hz), 5.09 (1H, s), 5.95 (1H, t, J 2.0 Hz), 6.39(2H, d, J 8.5 Hz), 6.99 (1H, s), 7.26 (4H, m), 7.61 (1H, d, J 8.6 Hz).

DESCRIPTION 16(3S,5R,6S)-7-(tert-Butoxycarbonyl)-6-phenyl-3-(2-(thiazol-5-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 13 (200 mg) and5-(tributylstannyl)-1,3-thiazole (Synthesis 1986, 757) (144 mg) andlithium chloride (80 mg) were suspended in dioxane (5 ml) and themixture was degassed and purged with nitrogen (x5, firestone valve).Tetrakis(triphenylphosphine)palladium(0) (50 mg) was added and themixture was repurged with nitrogen. The reaction mixture was heated atreflux for 4 hours. The mixture was diluted with water and the productwas extracted with ethyl acetate (3×20 ml). The organic layer was dried(brine, MgSO₄) and concentrated in vacuo and the residue was purified bymedium pressure chromatography on silica using 10% ethyl acetate inhexane as eluant to afford the compound as a clear oil (120 mg, 67%). ¹H NMR (250 MHz, CDCl₃) δ 1.37 (9H, s), 1.67 (3H, m), 2.03 (1H, m), 2.09(1H, dd, J 13.2, 8.6 Hz), 2.36 (1H, dd, J 13.2, 8.5 Hz), 2.89 (1H, m),3.52 (1H, qn, J 8.4 Hz), 3.66 (1H, t, J 8.3 Hz), 4.04 (1H, d, J 12.7Hz), 4.07 (1H, dd, J 8.5, 6.7 Hz), 5.22 (1H, s), 6.79 (1H, d, J 8.7 Hz),7.10 (1H, s), 7.30 (5H, m), 7.55 (2H, d, J 7.2 Hz), 7.76 (1H, s)

DESCRIPTION 17(3S,5R,6S)-7-(tert-Butoxycarbonyl)-6-phenyl-3-(2-(thien-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 13 and 2-(tributylstannyl)thiophene according to the methodillustrated in Description 16. MS (ES⁺) m/z 460 (M⁺ +1 (-56), 100%), 504(M⁺ +1, 70%).

DESCRIPTION 18(2S,3R)-1-tert-Butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol

O-Trimethylsilylpropargyl alcohol (24.51 ml, 20.47 g, 160 ml) was addedslowly to a cooled (-10° C.) solution of ethylmagnesium bromide (1M intetrahydrofuran, 160 ml, 160 mmol). The mixture was stirred at 0° C. for20 minutes, then at room temperature for 2 hours. The mixture was cooledto -10° C. and a solution of(2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1; 42.3g) in tetrahydrofuran (200 ml) was added dropwise over 30 minutes(internal temperature below -5° C.). The mixture was stirred at roomtemperature for 14 hours, poured into water (300 ml) and saturatedaqueous ammonium chloride (300 ml) and extracted with ethyl acetate(2×300 ml). The combined organic fractions were washed with brine (300ml), dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate (500 ml) and asolution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 160 ml,160 mmol) was added dropwise. The mixture was stirred at roomtemperature for 30 minutes, water (300 ml) was added, and the layerswere separated. The aqueous layer was extracted with ethyl acetate(2×300 ml) and the combined organic fractions were washed with water(300 ml) and brine (300 ml), dried (MgSO₄) and the solvent wasevaporated under reduced pressure to give the crude title compound as anorange oil (45 g). The crude material was purified by flash columnchromatography on silica gel, eluting with hexane/EtOAc (90:10increasing to 25:75) to give the title compound as an amber oil (32.2g). ¹ H NMR (CDCl₃) δ 7.53-7.55 (2H, m), 7.19-7.35 (3H, m), 5.56 (1H,s), 4.27 (2H, s), 3.99-4.03 (1H, m), 3.25 (1H, br s), 2.77-2.81 (1H, m),2.77 (1H, br s), 2.12-2.20 (1H, m), 1.91-1.99 (2H, m), 1.77-1.83 (1H,m), and 1.39 (9H, s).

DESCRIPTION 19(5R,6S)-7-(tert-Butoxycarbonyl)-6-phenyl-3-(tributylstannyl)-7-aza-1-oxa-spiro[4.5]dec-3-ene

Crude(2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol(Description 18; 45 g) was dissolved in toluene (750 ml) and degassedwith nitrogen. Tetrakis(triphenylphosphine) palladium (0) (2.30 g, 2.0mmol) in toluene (600 ml) was added and the mixture was degassed.Tributyltin hydride (35.78 ml, 38.71 g, 133 mmol) was added dropwiseover 15 minutes, with stirring and cooling (internal temperature below25° C.). The mixture was stirred at room temperature for 1 hour, thenthe solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (600 ml) and triphenylphosphine (34.88 g,133 mmol) was added. A solution of diethyl azodicarboxylate (20.94 ml,23.16 g, 133 mmol) in tetrahydrofuran (150 ml) was added dropwise withstirring and cooling and the mixture was stirred at room temperature for1 hour. The solvent was evaporated under reduced pressure, acetonitrile(600 ml) was added and the mixture was extracted with hexane (8×150 ml).The hexane fractions were combined and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with dichloromethane/ethyl acetate(100:0 increasing to 99:1) to give the title compound as a yellow oil(53.64 g, 67% from(2s,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine). ¹ H NMR(CDCl₃) δ 7.38-7.40 (2H, m), 7.15-7.25 (3H, m), 5.96 (1H, t, J 2.3 Hz),4.93 (1H, s), 4.63 (1H, dd, J 2.23, 12.9 Hz), 4.22 (1H, dd, J 2.23, 12.9Hz), 4.09-4.14 (1H, m), 3.09-3.17 (1H, m), 1.95-1.99 (1H, m), 1.83-1.86(1H, m), 1.72-1.76 (2H, m), 1.40-1.51 (6H, m), 1.38 (9H, s), 1.25-1.32(6H, m), and 0.86-0.99 (15H, m).

DESCRIPTION 20Z-(2S,3R)-1-tert-Butoxycarbonyl-3-(3-hydroxyprop-1-en-1-yl)-2-phenylpiperidin-3-ol

Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2g) was added to a solution of(2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol(Description 18; 32 g, 96.6 mmol) in ethyl acetate (300 ml) and themixture was stirred under hydrogen (1 atm.) for 4 hours. The mixture wasfiltered and the solvent was evaporated under reduced pressure to givethe title compound as an oil (32 g, 100%). ¹ H NMR (360 MHz, CDCl₃) δ7.42 (2H, d, J 7.6 Hz), 7.35-7.25 (3H, m), 5.83 (1H, d, J 12.3 Hz), 5.68(1H, dt, J 12.3, 6.0 Hz), 5.06 (1H, s), 4.27 (1H, m), 4.12 (2H, m), 3.32(1H, m), 3.13 (1H, s), 2.28 (1H, t, J 5.9 Hz), 2.02 (1H, m), 1.92-1.78(3H, m), and 1.32 (9H, s). m/z (ES⁺) 334 (M+1).

DESCRIPTION 21(5R,6S)-7-(tert-Butoxycarbonyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

Diethyl azodicarboxylate (18.2 ml, 115 mmol) in THF (100 ml) was addeddropwise to a solution ofZ-(2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxyprop-1-en-1-yl)-2-phenylpiperidin-3-ol(Description 20; 32 g, 96 mmol) and triphenylphosphine (30.2 g, 115mmol) in THF (700 ml). The mixture was stirred at 0° C. for 30 minutesthen at room temperature for 1.5 hours. The solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with hexane/ethyl acetate (95:5increasing to 80:20) to give the title compound as a colorless solid(23.4 g, 77%). MS (ES⁺) m/z 316 (M⁺ +1, 100%). ¹ H NMR (CDCl₃) δ 7.45(2H, d, J 7.4 Hz), 7.27 (2H, t, J 7.4 Hz), 7.20 (1H, t, J 7.4 Hz), 6.03(1H, dt, J 6.1, 2.0 Hz), 5.68 (1H, dt, J 6.1, 2.0 Hz), 5.06 (1H, s),4.61 (1H, dt, J 13.1, 2.0 Hz), 4.32 (1H, dt, J 13.1, 2.0 Hz), 4.08 (1H,m), 3.05 (1H, m), 2.05 (1H, m), 1.75 (3H, m), and 1.37 (9H, s).

DESCRIPTION 22(3R,5R,6S)-3-(2-Benzyloxy-5-(trifluoromethoxy)phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

a) 2-Benzyloxy-5-(trifluoromethoxy)benzene

Benzyl bromide (66.17 ml, 95.35 g, 0.56 mol) was added to a mixture of4-(trifluoromethoxy)phenol (90.26 g, 0.51 mol) and potassium carbonate(140.97 g, 1.2 mol) in dimethylformamide (160 ml) and the mixture wasstirred at room temperature for 72 hours. The mixture was poured intowater (1.5 liters) and extracted with ethyl acetate (3×500 ml). Thecombined organic fractions were washed with aqueous sodium carbonate(saturated, 500 ml), dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the title compound as a colorless solid (133.5g, 99%). ¹ H NMR (360 MHz, CDCl₃) δ 7.39 (5H, m), 7.14 (2H, d, J 9.0Hz), 6.95 (2H, d, J 9.0 Hz), and 5.05 (2H, s).

b) 2-Benzyloxy-5-(trifluoromethoxy)iodobenzene

Iodine (71.96 g, 0.28 mol) in chloroform was added dropwise to a mixtureof 2-benzyloxy-5-(trifluoromethoxy)benzene (Description 22a, 73.06 g,0.27 mol) and silver trifluoroacetate (71.57 g, 0.32 mol) indichloromethane and the mixture was stirred at room temperature for 18hours. The mixture was filtered through celite, washed with aqueoussodium thiosulfate (5%, 2×2 liters), dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with hexane/EtOAc, to givethe title compound as a colorless oil (108.03 g), containing 11%unreacted 2-benzyloxy-5-(trifluoromethoxy)iodobenzene. ¹ H NMR (360 MHz,CDCl₃) δ 7.67 (1H, d, J 2.8 Hz), 7.40 (5H, m), 7.16 (1H, dd, J 8.9, 2.8Hz), 6.82 (1H, d, J 8.9 Hz), and 5.14 (2H, s).

c)(3R,5R,6S)-3-(2-Benzyloxy-5-(trifluoromethoxy)phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

A mixture of 2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Description22b, 21.8 g, 55.2 mmol),(5R,6S)-7-(tert-butoxycarbonyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene(Description 21, 7.0 g, 22.1 mmol), tetra-n-butylammonium chloride (6.18g, 22.2 mmol), lithium chloride (9.35 g, 0.22 mol) and potassium formate(5.64 g, 67.0 mmol) in dimethylformamide (100 ml) was degassed with afirestone valve (x5) and purged with nitrogen. Palladium acetate (491mg, 2.2 mmol) was added and the mixture was degassed with a firestonevalve (x5). The mixture was stirred at 60° C. for 15 hours, then further2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Description 22b, 4.32 g,11.0 mmol), potassium formate (2.78 g, 33.5 mmol) and palladium acetate260 mg, 1.1 mmol) were added. The mixture was stirred at 60° C. for 22hours, cooled and filtered. The solvent was evaporated under reducedpressure, water (600 ml) was added and the mixture was extracted withethyl acetate (2×300 ml). The combined organic fractions were washedwith brine (300 ml), dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with hexane/CH₂ Cl₂ (75:25increasing to 0:100) then CH₂ Cl₂ /EtOAc (95:5), to give the titlecompound (9.42 g, 73%). ¹ H NMR (360 MHz, CDCl₃) δ 7.56 (2H, d, J 7.7Hz), 7.40-7.20 (8H, m), 7.14 (1H, d, J 2.0 Hz), 7.00 (1H, dd, J 8.9, 2.0Hz), 6.88 (1H, d, J 8.9 Hz), 5.30 (1H, s), 5.08 (2H, s), 4.27 (1H, m),3.97 (1H, m), 3.87 (2H, m), 2.78 (1H, m), 2.56 (1H, m), 2.15 (1H, m),1.96 (1H, m), 1.67 (3H, m), and 1.42 (9H, s).

DESCRIPTION 23(3R,5R,6S)-7-(tert-Butoxycarbonyl)-3-(2-hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

Palladium on carbon (10%, 0.59 g) was added to a solution of thecompound of Description 22c (6.10 g, 10.5 mmol) in methanol-water (99:1,200 ml) and the mixture was stirred under hydrogen (50 psi.) for 72hours. The mixture was filtered, washing with ethanol, and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂ Cl₂ /EtOAc (99:1increasing to 90:10) to give the title compound. ¹ H NMR (360 MHz,CDCl₃) δ 7.70 (2H, d, J 7.3 Hz), 7.33 (2H, t, J 7.3 Hz), 7.26 (1H, d, J7.3 Hz), 7.05 (1H, br s), 6.96 (2H, m), 6.82 (1H, d, J 9.4 Hz), 5.43(1H, s), 4.27 (1H, m), 4.01 (1H, m), 3.95 (1H, m), 3.73 (1H, m), 2.73(2H, m), 2.33 (1H, m), 1.87-1.58 (4H, m), and 1.50 (9H, s).

DESCRIPTION 24(3R,5R,6S)-7-(tert-Butoxycarbonyl)-6-phenyl-3-(5-(trifluoromethoxy)-2-(trifluoromethylsulfonyloxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

Trifluoromethanesulphonic anhydride (0.68 ml) was added dropwise to astirred, cooled (0° C.) solution the compound of Description 23 (1 g) inpyridine (4 ml). The mixture was allowed to warm to room temperature andstirred for 16 hours. Further trifluoromethanesulphonic anhydride (0.34ml) was added and the mixture was stirred at room temperature for 2hours. Aqueous copper (II) sulphate was added and the mixture wasextracted with ethyl acetate (3×50 ml). The combined organic fractionswere washed with brine, dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by MPLC on silica gel,eluting with hexane/EtOAc (90:10) to give the title compound as acolourless oil. ¹ H NMR (360 MHz, CDCl₃) δ 1.43 (9H, s), 1.78 (3H, m),2.25 (2H, m), 2.78 (2H, m), 385 (2H, m), 4.02 (1H, dd, J 13.7 Hz), 4.27(1H, dd, J 8.7, 6.9 Hz), 5.30 (1H, s), 7.27 (1H, m), 7.31 (5H, m), and7.57 (2H, d, J 7.6 Hz).

DESCRIPTION 25(3R,5R,6S)-7-(tert-Butoxycarbonyl)-3-(2-(fur-3-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

a) 3-(Tributylstannyl)furan

3-Bromofuran (1.23 ml) was dissolved in diethyl ether (15 ml) and cooledto -76° C. Butyllithium (8.5 ml, 1.6M in hexane) was added dropwiseensuring the temperature remained below -60° C. After stirring for 15minutes, tributyltin chloride (3.69 ml) was added. The reaction wasstirred at -76° C. for 1 hour. The reaction was diluted with aqueoussodium hydrogencarbonate (20 ml) and the product extracted with diethylether (3×20 ml). The combined organic fractions were dried (brine,MgSO₄) and concentrated in vacuo. The residue was purified bychromatography on silica eluting with hexane to yield the title compoundas a colourless oil. ¹ H NMR (CDCl₃, 360 MHz), δ 0.91 (9H, t, J 8.9 Hz),1.03 (6H, t, J 10.4 Hz), 1.34 (6H, sx, J 7.3 Hz), 1.58 (6H, m), 6.35(1H, d, J 1.5 Hz), 7.23 (1H, s), 7.56 (1H, t, J 1.4 Hz).

b)(3R,5R,6S)-7-(tert-Butoxycarbonyl)-3-(2-(fur-3-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

The triflate of Description 24, (300 mg), 3-(tributylstannyl)furan (205mg), lithium chloride (121 mg) and tetrakis(triphenylphosphine)palladium(0) (50 mg) were dissolved in dioxane (5 ml). The reaction waspurged (5x vac/N₂) and heated at 110° C. for 16 hours. The catalyst wasremoved by filtration and the filtrate concentrated in vacuo. Theresidue was dissolved in acetonitrile (10 ml) and the solution washedwith hexane (20 ml). The product was extracted with acetonitrile (3×10ml). To the combined acetonitrile fractions was added potassium fluoride(3 ml×5% methanolic soln.). The precipitate formed was removed byfiltration. The filtrated was concentrated in vacuo and the residuepurified by chromatography on silica eluting with 10% ethyl acetate inhexane to yield the title compound as an oil. MS (ES⁺) m/z 444 (M+H-100,65%), 488 (M+H-56, 100%), 544 (M+H, 2%). ¹ H NMR (CDCl₃, 360 MHz), δ1.49 (9H, s), 1.72 (1H, m), 1.84 (2H, m), 2.28 (1H, td, J 12.2 Hz), 2.63(1H, dd, J 12.3, 8.0 Hz), 2.75 (1H, td, J 12.2, 5.0 Hz), 3.89 (3H, m),3.97 (1H, d, J 10.2 Hz), 4.13 (1H, m), 5.23 (1H, s), 6.46 (1H, s), 7.8(1H, d, J 8.2 Hz), 7.27 (5H, m), 7.47 (1H, s), 7.50 (1H, s), 7.55 (2H,d, J 7.8 Hz).

DESCRIPTION 26(3R,5R,6S)-7-tert-Butoxycarbonyl-6-phenyl-3-(2-(pyrid-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 2-(tributylstannyl)pyridine according to the methodillustrated in Description 25. ¹ H NMR (CDCl₃, 360 MHz), δ 1.39 (9H, s),1.61 (1H, m), 1.69 (1H, m), 1.79 (1H, d, J 12.7 Hz), 1.88 (1H, dd, J12.9, 9.3 Hz), 2.48 (1H, m), 2.63 (1H, dd, J 12.9, 8.3 Hz), 2.74 (1H,td, J 12.9. 3.8 Hz), 3.76 (1H, qn, J 7.8 Hz), 3.92 (2H, m), 4.14 (1H, t,J 7.6 Hz), 5.15 (1H, s), 7.17 (1H, d, J 10.1 Hz), 7.25 (1H, d, J 11.8Hz), 7.30 (3H, m), 7.37 (2H, m), 7.53 (2H, d, J 7.7 Hz), 7.79 (1H, dd, J9.2, 1.6 Hz), 8.40 (1H, d, J 7.9 Hz), 8.64 (1H, m)

DESCRIPTION 27(3R,5R,6S)-7-tert-Butoxycarbonyl-6-phenyl-3-(2-(pyrid-3-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 3-(tributylstannyl)pyridine according to the methodillustrated in Description 25. MS (ES⁺) m/z 555 (M⁺ +1, 100%) ¹ H NMR(360 MHz, CDCl₃) δ 1.38 (9H, s), 1.49-1.89 (4H, m), 2.25 (1H, dt, J13.0, 5.0 Hz), 2.58 (1H, dd, J 13.0, 8.4 Hz), 2.74 (1H, dt, J 13.0, 3.7Hz), 3.52 (1H, qn, J 8.4 Hz), 3.88 (1H, t, J 8.87 Hz), 3.95 (1H, mc),4.09 (1H, t, J 7.5 Hz), 5.10 (1H, s), 7.15-7.31 (5H, m), 7.37-7.42 (2H,m), 7.49 (2H, d, J 7.8 Hz), 7.60 (1H, dd, J 7.76 1.8 Hz), 8.54 (1H, s),(1H, d, J 4.0 Hz).

DESCRIPTION 28(3R,5R,6S)-7-tert-Butoxycarbonyl-6-phenyl-3-(2-(pyrid-4-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 4-(trimethylstannyl)pyridine according to the methodillustrated in Description 25. MS (ES⁺) m/z 555 (M⁺ +1, 100%) ¹ H NMR(250 MHz, CDCl₃), δ 1.38 (9H, s), 1.58-1.89 (4H, m), 2.28 (1H, dt, J12.9, 5.0 Hz), 2.60 (1H, dd, J 12.9, 6.5 Hz), 2.60 (1H, dt, J 12.9, 3.7Hz), 3.54 (1H, qn, J 8.0 Hz), 3.43-3.60 (2H, m), 4.10 (1H, t, J 7.2 Hz),5.12 (1H, s), 7.14-7.31 97H, m), 7.37 (1H, s), 7.50 (2H d, J 7.3 Hz),8.70 (2H, d, J 7.3 Hz).

DESCRIPTION 29(3R,5R,6S)-7-tert-Butoxycarbonyl-3-(2-(oxazol-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 2-(tributylstannyl)oxazole (EP-0 590 970-A) accordingto the method illustrated in Description 25. MS (ES) m/z 546 (M⁺ +1,60%), 489 (M⁺ -56, 100%). ¹ H NMR (360 MHz, CDCl₃) δ 1.47 (9H, s),1.58-1.80 (3H, m), 2.24 (1H, dt, J 13.0, 5.0 Hz), 2.76-2.85 (2H, m),3.92-4.00 (2H, m), 4.13 (1H, dd, J 9.0, 7.5 Hz), 4.61-4.67 (2H, m), 5.36(1H, s), 7.17 (1H, dd, J 8.0, 1.1 Hz), 7.22-7.34 (4H, m), 7.40 (1H, d, J2.0 Hz), 7.60 (2H, d, J 8.5 Hz), 7.78 (1H, s), 7.93 (1H, d, J 8.5 Hz).

DESCRIPTION 30(3R,5R,6S)-7-tert-Butoxycarbonyl-6-phenyl-3-(2-(pyrazin-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 2-(tributylstannyl)pyrazine (Synth. Commun. 1992,22(12) 1757-62) according to the method illustrated in Description 25.MS (ES) m/z 556 (M⁺ +1, 60%), 500 (m⁺ -56, 100%), 456 (M⁺ -100, 10%). ¹H NMR (250 MHz, CDCl₃) δ 1.39 (9H, s), 1.62-1.94 (4H, m), 2.35 (1H, dt,J 12.5, 5.0 Hz), 2.64-2.81 (2H, m), 3.67-3.79 (1H, m), 3.89-3.98 (1H,m), 4.18 (1H, t, J 7.5 Hz), 5.16 (1H, s), 7.18-7.55 (8H, m), 8.58-8.61(1H, m), 8.78 (1H, s).

DESCRIPTION 31(3R,5R,6S)-7-tert-Butoxycarbonyl-6-phenyl-3-(2-(pyrimidin-5-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Suzuki coupling of the compound ofDescription 24 and 5-(pyrimidin-yl)boronic acid (Chem. Scr. 1986, 26(2)305-9) according to the following method: The triflate (Desc. 24, 200mg), lithium chloride (80 mg), sodium carbonate (1M aq., 1 ml), and5-(pyrimidin-yl)boronic acid (44 mg) were suspended in DME (5 ml) atroom temperature. The mixture was then degassed 5 times and purged withnitrogen before adding tetrakistriphenylphosphine palladium(0) (50 mg, 5mol %) and repeating the degassing procedure. The mixture was heated atreflux for 48 hours. The mixture was then partitioned between water andethyl acetate and the organic layer was then washed with brine, dried(MgSO₄), filtered and evaporated, to give a crude oil which was purifiedby medium pressure chromatography on silica eluting with 30% ethylacetate in hexane to afford a colourless oil (48% yield). MS (ES) m/z556 (M⁺ +1, 45%), 500 (M⁺ -56, 50%). ¹ H NMR (250 MHz, CDCl₃) δ 1.47(9H, s), 1.52-1.96 (4H, m), 2.28 (1H, dt, J 12.5, 5.3 Hz), 2.60 (1H, dd,J 12.5, 8.5 Hz), 2.77 (1H, dd, J 13.0, 3.8 Hz), 3.34-3.52 (1H, m),3.87-3.99 (2H, m), 4.08-4.16 (1H, m), 5.11 (1H, s), 7.18-7.51 (8H, m),8.68 (2H, s), 9.28 (1H, s).

DESCRIPTION 32(3R,5R,6S)-7-(tert-Butoxycarbonyl)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 2-(tributylstannyl)furan according to the methodillustrated in Description 25. MS (ES) m/z 544 (M⁺ +1, 80%), 488 (M⁺-56, 100%). ¹ H NMR (360 MHz, CDCl₃) δ 1.44 (9H, s), 1.59-1.66 (3H, m),1.87 (1H, dd, J 13.0, 8.6 Hz), 2.25 (1H, dt, J 13.0, 5.0 Hz), 2.71 (1H,dd, J 13.3, 8.3 Hz), 2.78 (1H, dt, J 13.3, 3.6 Hz), 3.91-4.03 (3H, m),4.19 (1H, dd, J 7.2, 6.5 Hz), 5.30 (1H, s), 6.50 (2H, s) 7.12 (1H, dd, J8.6, 1.0 Hz), 7.21-7.33 (4H, m), 7.50-7.59 (4H, m).

DESCRIPTION 33

(3R,5R,6S)-3-[2-(Ethen-1-yl)-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4,5]decane

A mixture of the triflate of Description 24 (200 mg), vinyltributyltin(0.11 ml), lithium chloride (80 mg) andtetrakis(triphenylphosphine)palladium (0) (50 mg) in dioxane (5 ml) wasdegassed using a firestone valve (×5). The mixture was heated at 110° C.for 2 hours, cooled and filtered. The solvent was evaporated underreduced pressure and the residue was dissolved in acetonitrile. Themixture was washed with hexane (30 ml). The mixture was extracted withethyl acetate (3×30 ml) and the combined organic fractions were washedwith brine, dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by MPLC on silica gel, eluting withhexane/EtOAc (85:15) to give the title compound as an oil. ¹ H NMR (360MHz, CDCl₃) d 1.47 (9H, s), 1.62 (3H, m), 1.83 (1H, m), 2.25 (1H, td),2.63 (1H, dd, J=7.5 Hz), 2.76 (1H, td), 3.82 (1H, q), 3.90 (1H, t, J=8.3Hz), 3.98 (1H, dd), 4.24 (1H, J=7.3 Hz), 5.36 (2H, m), 5.57 (1H, d,J=16.7 Hz), 6.97 (1H, dd, J=11.0, 16.9 Hz), 7.15 (1H, d), 7.25 (1H, s),7.33 (1H, m), 7.35 (2H, m), 7.76 (1H, d, J=8.5 Hz), and 7.60 (2H, d,J=7.6 Hz).

DESCRIPTION 34

(3R,5R,6S)-3-(2-Formyl-5-(trifluoromethyoxy)phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-1-oxa-7-aza-spiro[4,5]decane

The styrene of description 33 (420 mg) was dissolved in dichloromethane(10 ml) and methanol (4 ml) was added. The reaction was cooled to -76°C. and purged with nitrogen. A steady stream of oxygen was bubbledthrough the reaction and the reaction was treated with ozone for 1 hour.The reaction was purged with oxygen for 15 minutes followed by nitrogenfor 15 minutes. Dimethyl sulphide (0.3 ml) was added and the reactionstirred at room temperature overnight. The reaction was concentrated invacuo and the residue purified on silica eluted with 15% ethyl acetatein hexane to yield the above compound as an oil. ¹ H NMR (CDCl₃, 360MHz), δ1.48 (9H, s), 1.55 (2H, m), 1.72 (1H, d, J=9.5 Hz), 1.85 (1H, dd,J=13.0 8.4 Hz), 2.25 (1H, m), 2.77 (2H, m), 3.97 (2H, m), 4.27 (1H, dd,J=9.0, 7.2 Hz), 4.53 (1H, qn, J=7.2 Hz), 5.36 (1H, s), 7.26 (2H, m),7.34 (3H, m), 7.59 (2H, d, J=7.6 Hz), 7.87 (1H, d, J=8.5 Hz), 10.26 (1H,s), MS (EI+) m/z 450 (M+H-56, 15%), 406 (M+H-100, 100%).

DESCRIPTION 35

(3R,5R,6S)-3-(2-Oxazol-5-yl)-5-(trifluoromethoxy)phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-1-oxa-7-aza-spiro[4,5]decane

The aldehyde of Description 34 (150 mg), tosylmethyl isocyanide (58 mg)and potassium carbonate (250 mg) were dissolved in methanol (6 ml) andheated at reflux (65° C.) for one hour. The reaction was concentrated invacuo and the residue dissolved in dichloromethane (10 ml). The solutionwas washed with water (20 ml) and the product extracted withdichloromethane (3×10 ml). The combined organic fractions were dried(brine, MgSO₄) and concentrated in vacuo. The residue was purified onsilica eluted with 20% ethyl acetate in hexane, to yield the titleproduct as an oil. ¹ H NMR (CDCl₃, 360 MHz), δ 1.45 (9H, s), 1.55 (2H,m), 1.75 (1H, m), 1.85 (1H, dd, J=12.8, 8.6 Hz), 2.26 (1H, td), 2.73(1H, dd, J=12.9, 8.1 Hz), 2.77 (1H, dd, J=13.3 Hz), 3.82 (1H, qn), 3.97(2H, t, J=7.0 Hz), 4.19 (1H, dd, J=7.2, 8.9 Hz), 5.29 (1H, s), 7.16 (1H,d, J=8.3 Hz), 7.24 (2H, m), 7.32 (2H, t, J=7.0 Hz), 7.37 (1H, s), 7.52(1H, d, J=8.5 Hz), 7.57 (2H, d, J=7.5 Hz), 8.03 (1H, s), M/Z (ES+) 445(M+H-100, 100%), 489 (M+H-56, 20%), 545 (M+H, 30%).

DESCRIPTION 36

(3R,5R,6S)-3-(2-(5-Methylfur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-(tert-butoxycarbonyl)aza-1-oxa-spiro[4,5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 5-methyl-2-tributylstannylfuran (Bull. Chim. Sc. Jpn.1992, 65, 2366) according to the method illustrated in Description 25.MS (ES) m/z 503 (M⁺ H-56, 7%), 458 (M+H-100, 100%), ¹ H NMR (360 MHz,CDCl₃) 1.43 (9H, s), 1.58-1.79 (3H, m), 1.88 (1H, dd, J=13.0, 8.3 Hz),2.24 (1H, dt, J=12.6, 5.0 Hz), 2.37 (1H, s), 2.69 (1H, dd, J=12.6, 8.3Hz), 2.81 (1H, dt, J=13.3, 4.0 Hz), 3.61-3.64 (1H, m), 3.90-4.06 (3H,m), 4.20 (1H, dd, J=7.9, 7.2 Hz), 5.30 (1H, s), 6.08 (1H, dd, J=2.2, 0.7Hz), 6.38 (1H, d, J=3.2 Hz), 7.08-7.11 (1H, m), 7.21-7.33 (4H, m),7.51-7.58 (3H, m).

DESCRIPTION 37

(3R,5R,6S)-3-(2-(5-Methylisoxazol-4-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-(tert-butoxycarbonyl)aza-1-oxa-spiro[4,5]decane

This compound was prepared from the Stille coupling of the compound ofDescription 24 and 5-methyl-3-tributylstannylfuran (Heterocycles 1996,431303) according to the method illustrated in Description 25. MS (ES) m/z559 (M⁺ +H, 2%), 459 (M+H-100, 100%) ¹ H NMR (360 MHz, CDCl₃) d 1.42(9H, s), 1.58-1.86 (3H, m), 2.19(3H, s), 2.20-2.33 (1H,m), 2.57 (1H, dd,J=12.8, 8.3 Hz), 2.57 (1H, dd, J=12.8, 8.3 Hz), 2.77 (1H, dt, J=13.3,3.8 Hz), 3.37-3.50 (1H, m), 3.86 (1H, t, J=8.3 Hz), 3.96(1H, dd,J=13.5,4.5), 4.06-4.16 (1H, m), 5.15 (1H, s) 7.12-7.35 (6H, m),7.50-7.53 (2H, m), 8.31 (1H,s).

DESCRIPTION 38

(3R,5R,6S)-3-(Thiophen-2-yl-5-(trifluoromethoxy)phenyl)-7-(tert-butoxycarbonyl)-6-phenyl-1-oxa-7-aza-spiro[4,5]decane

The triflate of Description 24 (300 mg), thiophene-3-boronic acid (74mg), lithium chloride (121 mg), water (1 ml) and sodium carbonate (152mg) were suspended in ethylene glycol dimethyl ether (6 ml) and thereaction purged with vacuum/nitrogen, via a firestone valve. Palladiumtetrakistriphenylphosphine (50 mg) was added and the reaction purgedagain (×3). The reaction was heated at reflux for 16 hours. The reactionwas filtered and the filtrate concentrated in vacuo. An aqueous work upwas performed and the product extracted with ethyl acetate. The combinedorganic phase was dried (brine, MgSO₄) and concentrated in vacuo. Theresidue was purified on silica eluted with 5% ethyl acetate in hexane. ¹H NMR (CDCl₃, 360 MHz), δ 1.41 (9H, s), 1.71 (1H, m), 1.84 (2H, m), 2.25(2H, m), 2.60 (1H, dd, J=12.9, 8.3 Hz), 2.75 (1H, td, J=13.2, 3.7 Hz),3.75 (1H, qn, J=8.1 Hz), 3.86 (1H, t, J=7.7 Hz), 3.95 (1H, dd, J=13.9Hz), 4.11 (1H, t, J=8.7 Hz), 5.17 (1H, s), 7.05 (1H, dd, J=6.2, 1.3 Hz),7.10 (1H, d, J=9.7 Hz), 7.28 (6H, m), 7.40 (1H, dd, J=4.8 Hz), 7.53 (2H,d, J=7.5 Hz). M/Z (ES+) 560 (M+H, 5%), 504 (M+H-56, 100%), 460 (M+H-100,25%).

EXAMPLE 1

(5R,6S)-3-(5-Methoxy-2-(5-trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

(5R,6S)-7-(tert-butoxycarbonyl)-3-(5-methoxy-2-(5-trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene(0.5 g, 0.9 mmol; Desc. 8) was dissolved in 3N methanolic HCl (30 ml)and stirred at ambient temperature for 14 hours. The solvent wasevaporated in vacuo, and the residue partitioned between aqueoussaturated potassium carbonate (50 ml) and ethyl acetate (50 ml). Theorganic layer was washed with brine (50 ml), dried over magnesiumsulphate and the solvent removed in vacuo. Medium pressurechromatography on silica eluting with 10% methanol/dichloromethaneafforded the title compound as a clear oil (350 mg), 85%) MS (ES⁺) m/z458 (M⁺ +H, 100%). ¹ H NMR (250 MHz, CDCl₃) δ 1.56 (3H, m), 1.95 (1H,m), 2.69 (1H, dt, J 2.7 Hz, J 12.5 Hz), 2.83 (1H, broad s), 3.21 (1H, m)3.51 (1H, s), 3.80 (1H, s) 4.15 (1H, dd, J 2.2 Hz, J 12.3 Hz), 4.42 (1H,dd, J 2.2 Hz, J 12.3 Hz), 4.92 (1H, t, J 2.1 Hz), 6.27 (1H, d, J 2.8Hz), 6.88 (1H, dd, J 2.8 Hz, J 8.8 Hz), 7.17 (1H, d, J 8.8 Hz), 7.25(5H, m).

EXAMPLE 2

(3S,5R,6S)-3-(5-Methoxy-2-(5-(trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

(3S,5R,6S)-3-(5-Methoxy-2-(5-trifluoromethyl)tetrazol-1-yl)phenyl-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene(0.35 g, 0.7 mmol; Ex.1) was dissolved in methanol (10 ml) and glacialacetic acid (1 ml) and 10% palladium hydroxide/carbon was added. Thereaction mixture was hydrogenated at 40 psi for 15 hours. The solutionwas filtered and evaporated in vacuo. The residue was partitionedbetween aqueous saturated potassium carbonate (50 ml) and ethyl acetate(50 ml). The organic layer was washed with brine (50 ml), dried overmagnesium sulphate and the solvent evaporated in vacuo. Medium pressurechromatography eluting with 10% methanol/dichloromethane afforded thetitle compound (105 mg, 34%). MS (ES⁺) m/z 460 (M⁺ +H, 100%). ¹ H NMR(250 MHz, CDCl₃) δ 1.45 (1H, dt, J 13.2 Hz, J 3.9 Hz), 1.51 (1H, m),1.81 (2H, t, J 10.5 Hz), 1.94 (2H, m), 2.55 (1H, m), 2.77 (1H, dt, J12.4 Hz, J 2.8 Hz), 3.20 (1H, m), 3.27 (1H, q, J 9.1 Hz), 3.59 (3H, s),3.69 (1H, s), 3.91 (1H, t, J 7.5 Hz), 5.87 (1H, d, J 2.7 Hz), 6.78 (1H,dd, J 8.8 Hz, J 2.7 Hz), 7.04 (1H, d, J 8.8 Hz), 7.35 (3H, m) 7.53 (2H,m).

EXAMPLE 3

(5R,6S)-3-(5-Methoxy-2-tetrazol-1-yl)phenyl-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

This compound was prepared and purified from the compound of Description10 according to the method of Example 1, to afford the title compound asa white foam (170 mg, 55%) m/z (CI⁺) 390 (M⁺ +H, 100%). ¹ H NMR (360MHz, CDCl₃) δ 1.60 (2H, m), 1.76 (1H, m), 1.95 (1H, m), 2.62 (1H, broads), 2.73 (1H, dt, J 2.6 Hz, J 12.7 Hz), 3.21 (1H, m), 3.63 (1H, s), 3.80(3H, s), 4.0 (1H, dd, J 2.2 Hz, J 12.5 Hz), 4.47 (1H, dd, J 2.2 Hz, J12.5 Hz), 5.02 (1H, t, J 2.1 Hz), 6.42 (1H, d, J 2.8 Hz), 6.88 (1H, dd,J 2.9 Hz, J 8.8 Hz), 7.20 (1H, d, J 8.8 Hz), 7.30 (5H, m), 8.04 (1H, s).

EXAMPLE 4

(3S,5R,6S)-3-(5-Methoxy-2-(tetrazol-1-yl)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decanehydrochloride

This compound was prepared from the product of Example 3 according tothe procedure described in Example 2 to afford the title compound as itsfree base. The hydrochloride salt was made and recrystallized from hotethyl acetate/methanol to afford the final compound as a white solid (50mg). MS (ES⁺) m/z 392 (M⁺ +H, 100%). ¹ H NMR (360 MHz, d₆ -DMSO) δ 1.70(4H, m), 1.92 (1H, m), 3.00 (1H, m), 3.18 (3H, m) 3.62 (3H, s), 3.94(1H, t, J 8.0 Hz), 4.48 (1H, d, J 11.2 Hz), 5.85 (1H, d, J 2.6 Hz), 6.93(1H, dd, J 2.8 Hz, J 8.8 Hz), 7.37 (1H, d, J 8.8 Hz), 7.54 (5H, m), 9.71(1H, s).

EXAMPLE 5

(5R,6S)-3-(Fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene

This compound was prepared from the compound of Description 15 accordingto the method illustrated in Example 1. MS (ES⁺) m/z 442 (M⁺ +1, 100%).¹ H NMR (250 MHz, CDCl₃), δ1.78 (4H, m), 2.83 (1H, td, J 12.1 Hz), 3.27(1H, dd, J 13.4 Hz), 3.78 (1H, s), 4.12 (2H, m), 4.47 (1H, dd, J 12.3,2.1 Hz), 5.61 (1H, t, J 2.12 Hz), 5.91 (1H, d, J 3.4 Hz), 6.32 (1H, dd,J 3.4, 1.8 Hz), 6.49 (1H, s), 7.11 (1H, d, J 8.6 Hz), 7.28 (3H, m), 7.39(2H, m), 7.57 (1H, d, J 8.7 Hz).

EXAMPLE 6

(3S,5R,6S)-3-(2-Fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 14 (52 mg) was dissolved in a solution ofmethanolic hydrogen chloride (20 ml, 2M) and stirred at room temperaturefor 2 hours. The reaction was evaporated to dryness and the residue wasrecrystallised from hot ethyl acetate to yield the title compound. MS(ES⁺) m/z 444 (M⁺ +1, 100%). ¹ H NMR (MeOD, 500 MHz), δ 1.87 (3H, m),2.12 (1H, d, J 13.7 Hz), 2.18 (1H, dd, J 12.9, 4.8 Hz), 2.26 (1H, m),3.24 (1H, td, J 10.1, 2.7 Hz), 3.43 (2H, m), 4.03 (1H, qn, J 10.8 Hz),4.20 (1H, t, J 8.2 Hz), 4.68 (1H, s), 6.13 (1H, s), 6.58 (2H, m), 7.15(1H, d, J 7.5 Hz), 7.48 (1H, d, J 8.6 Hz), 7.57 (5H, m), 7.66 (1H, s).

EXAMPLE 7

(3S,5R,6S)-6-Phenyl-3-(2-(thiazol-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 16 was deprotected according to the methodillustrated in Example 6 to afford the title compound as thehydrochloride salt. MS (ES⁺) m/z 461 (M+H, 100%) ¹ H NMR (500 MHz,CDCl₃), δ 1.53 (1H, t, J 10.5 Hz), 1.67 (1H, d, J 14.0 Hz), 1.85 (4H,m), 2.35 (1H, d, J 13.6 Hz), 2.85 (1H, d, J 11.1 Hz), 3.26 (1H, t, J 9.2Hz), 3.41 (1H, d, J 11.0 Hz), 3.52 (1H, t, J 8.9 Hz), 3.99 (2H, d, J 8.0Hz), 5.89 (1H, s), 6.98 (1H, d, J 8.3 Hz), 7.22 (1H, d, J 8.5 Hz), 7.37(2H, t, J 7.5 Hz), 7.46 (1H, t, J 7.3 Hz), 7.64 (2H, m), 9.36 (1H, s),10.32 (1H, s).

EXAMPLE 8

(3S,5R,6S)-6-Phenyl-3-(2-(thien-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 17 was deprotected according to the methodillustrated in Example 6 to afford the title compound as thehydrochloride salt. MS (ES⁺) m/z 461 (M⁺ +1, 100%). ¹ H NMR (250 MHz,CDCl₃) δ 1.52 (1H, t, J 10.9 Hz), 1.59 (2H, s), 1.65 (1H, d, J 14.2 Hz),1.83 (1H, t, J 11.4 Hz), 1.92 (2H, t, J 12.8 Hz), 2.35 (1H, d, J 13.8Hz), 2.85 (1H, d, J 11.6 Hz), 3.24 (1H, t, J 9.2 Hz), 3.42 (1H, d, J11.2 Hz), 3.68 (1H, qn, J 10.0 Hz), 4.00 (2H, q, J 8.3 Hz), 5.88 (1H,s), 6.86 (1H, s), 6.94 (1H, d, J 8.2 Hz), 7.06 (1H, t, J 3.5 Hz), 7.24(1H, t, J 6.5 Hz), 7.37 (2H, m), 7.46 (1H, t, J 7.4 Hz), 7.63 (1H, brs).

EXAMPLE 9

(3R,5R,6S)-3-(2-(Fur-3-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 25 (50 mg) was dissolved in dichloromethane(23 ml) and trifluoroacetic acid (1ml) was added. The reaction wasstirred at room temperature for 1 hour. The reaction was diluted withaqueous sodium hydrogencarbonate (10 ml) and the product extracted withdichloromethane. The combined dichloromethane fractions were dried(brine, MgSO₄) and concentrated in vacuo. The residue was purified bymedium pressure chromatography on silica eluting with 10% methanol indichloromethane to afford the free base as an oil: ¹ H NMR (CDCl₃, 360MHz), δ 1.59 (2H, m), 2.12 (3H, m), 2.45 (1H, m), 2.77 (1H, t, J 10.6Hz), 3.23 (1H, d, J 9.8 Hz), 3.50 (1H, d, J 15.2 Hz), 3.56 (1H, d, J10.4 Hz), 3.88 (1H, t, J 8.0 Hz), 5.98 (1H, s), 6.93 (1H, s), 7.01 (1H,d, J 9.1 Hz), 7.07 (1H, s), 7.11 (1H, d, J 8.4 Hz), 7.24 (4H, m), 7.36(3H, m). The free base (30 mg) was dissolved in ethyl acetate (5 ml) andhydrochloric acid in methanol (2 ml), 1M) was added. The reaction wasevaporated to dryness to yield a solid. The solid was recrystallisedfrom hot ethyl acetate to yield the product as a crystalline solid. MS(ES⁺) m/z 444, (M+H, 100%). ¹ H NMR (CDCl₃, 360 MHz), δ 1.69 (3H, m),2.10 (2H, m), 2.35 (2H, m), 2.79 (1H, td, J 11.8 Hz), 3.33 (1H, d, J11.9 Hz), 3.53 (1H, t, J 10.3 Hz), 3.81 (1H, s), 3.93 (1H, t, J 8.1 Hz),5.95 (1H, d, J 0.8 Hz), 6.90 (1H, s), 7.01 (2H, s), 7.11 (1H, d, J 9.2Hz), 7.23 (2H, dd, J 13.7, 6.2 Hz), 7.35 (2H, m), 7.48 (2H, d, J 7.4Hz).

EXAMPLE 10

(3R,5R,6S)-6-Phenyl-3-(2-(pyrid-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

The compound of Description 26 was deprotected according to the methodillustrated in Example 9 to afford the title compound as thedihydrochloride salt. free base: ¹ H NMR (CDCl₃, 360 MHz), δ 1.36 (3H,m), 2.08 (3H, m), 2.32 (1H, qn, J 8.3 Hz), 2.70 (1H, td, J 10.0, 2.6Hz), 3.19 (1H, m), 3.53 (1H, s), 3.58 (1H, dd, J 10.3, 8.5), 3.92 (1H,t, J 7.9 Hz), 6.93 (1H, d, J 7.8 Hz), 7.18 (4H, m), 7.88 (5H, m), 7.60(1H, td, J 7.7, 1.8 Hz), 8.47 (1H, s). dihydrochloride salt: MS (ES⁺)m/z 455 (M+H, 100%). ¹ H NMR (360 MHz, d₆ -DMSO,) δ 1.82 (3H, m), 2.01(2H, m), 2.13 (1H, dd, J 9.1, 8.2 Hz), 2.19 (1H, D, J 10.5 Hz), 3.02(1H, m), 3.19 (1H, D, J 9.8 Hz), 3.8, (2H, m), 4.23 (1H, d, J 10.9 Hz),7.19 (3H, M), 7.30 (3H, m), 7.59 (2H, m), 7.98 (1h, t, J 6.1 Hz), 8.54(1H, d, J 4.9 Hz), 8.70 (1H, m), 9.43 (1H, d, J 8.2 Hz).

EXAMPLE 11

(3R,5R,6S)-6-Phenyl-3-(2-pyrid-3-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 27 accordingto the method illustrated in Example 9 to afford the dihydrochloridesalt. MS (ES⁺) m/z 455 (M⁺ +1, 100%) ¹ H NMR (360 MHz, CDCl₃) δ1.52-1.76 (3H, m), 2.0-2.2 (5H, m), 2.73 (1H, t, J 12 Hz), 3.16-3.19(1H, m), 3.41 (1H, s), 3.58 (1H, t, J 9.0 Hz), 1H, t, J 8.0 Hz),7.02-7.26 (10H, m), 8.19 (1H, d, J 2.0 Hz), 8.62 (1H, dd, J 2.0, 2 Hz).

EXAMPLE 12

(3R,5R,6S)-6-phenyl-3-(2-(pyrid-4-yl)-5-(trifluoromethoxy)phenyl-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 28 accordingto the method illustrated in Example 9 to afford the dihydrochloridesalt. Anal. Calcd. for C₂₆ H₂₅ F₃ N₂ O₂.2HCl.H₂ O: C, 57.25; H, 5.36; N,5.13. Found: C, 57.48; H, 4.96; N, 5.28. MS (ES⁺) m/z 455 (M⁺ +1, 100%)

EXAMPLE 13

(3R,5R,6S)-6-phenyl-3-(2-oxazol-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 29 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.MS (ES) m/z 445 (M⁺ 1, 100%). ¹ H NMR (250 MHz, CDCl₃) δ 1.59-1.70 (3H,m). 2.01-2.17 (1H, m), 2.27 (1H, dd, J 13.0, 8.3 Hz), 2.76 (1H, t, J10.0 Hz), 3.12-3.27 (2H, m), 3.48 (1H, s), 3.64 (1H, t, J 9.0 Hz), 4.05(1H, t, J 7.7 Hz), 7.07-7.17 (1H, m), 7.20 (1H, brs), 7.26-7.33 (4H, m),7.48-7.52 (2H, m), 7.57 (1H,s), 7.75 (1H, d, 8.5 Hz).

EXAMPLE 14

(3R,5R,6S)-6-phenyl-3-(2-pyrazin-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 30 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.MS (ES) m/z 456 (M⁺ +1, 100%). ¹ H NMR (250 MHz, CDCl₃) δ 1.59-1.82 (3H,m), 2.04-2.24 (3H, m), 2.28-2.48 (1H, m), 2.72-2.82 (1H, m), 3.24-3.36(1H, m), 3.61 (1H, t, J 9.3 Hz), 3.76 (1H, s), 3.94-4.08 (1H,m),7.07-7.44 (8H, m), 8.30 (1H, s), 8.45 (1H, s), 8.58 (1H, s), 9.06 (1H,br), 10.08 (1H, br).

EXAMPLE 15

(3R,5R,6S)-6-phenyl-3-(2-pyrimidin-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 31 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.MS (ES) m/z 456 (M⁺ +1, 100%). ¹ H NMR (360 MHz, CDCl₃) δ 1.57-1.74 (3H,m), 1.80-1.91 (1H, m), 2.00-2.18 (3H, m), 2.70 (1H, t, J 12.0 Hz), 3.19(1H, d, J 10.4 Hz), 3.48 (1H, s), 3.62 (1H, dd, J 9.7, 8.6 Hz), 3.88(1H, t, J 8.0 Hz), 4.13 (1H, br, NH), 7.02 (1H, d, J 8.6 Hz), 7.05-7.16(5H, m), 7.22-7.28 (2H, m), 8.30 (2H, s), 9.25 (1H, s).

EXAMPLE 16

(3R,5R,6S)-3-(2-(Fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 32 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.MS (ES) m/z 444 (M⁺ +1, 100%). ¹ H NMR (250 MHz, CDCl₃) δ 1.64-1.78 (3H,m), 2.07 (1H, d, J 14.5 Hz), 2.19 (1H, dd, J 13.0, 8.5 Hz), 2.36-2.58(1H, m), 2.60-2.82 (2H, m), 3.32-3.38 (1H, m), 3.62 (1H, t, J 9.3 Hz),3.84 (1H, d, J 10.3 Hz), 4.02 (1H, t, J 8 Hz), 5.85 (1H, d, J 3.3 Hz),6.33 (1H, dd, J 3.3, 1.8 Hz), 6.96-7.04 (2H, m), 7.22-7.39 (5H, m),7.52-7.58 (2H, m).

EXAMPLE 17

*(3R,5R,6S)-3-(2-Fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-(1,2,4-triazol-3-ylmethyl)-aza-1-oxa-spiro[4.5]decane

The amine of Example 16 (100 mg) was dissolved in dimethylformamide (0.7ml) and treated with N-formyl-2-chloroacetimidrazone (32 mg) and heatedat 60° C. for 3 hours before diluting with xylene (10 ml) and heating at140° C. for a further 4 hours. The mixture was then filtered throughcelite washing with ethyl acetate. Evaporation yielded an off whitesolid which was purified by chromatography on silica(eluting with 10%methanol in dichloromethane) to give a white solid which wascrystallized from ether/ethyl acetate to yield the title compound aswhite crystals.(90 mg, 77%). MS (ES) m/z 525 (M⁺ +1, 100%). ¹ H NMR (360MHz, CDCl₃) d 2.08-2.30 (6H, m), 2.32-2.36 (1H, m), 2.54-2.68 (1H, m),2.96-3.06 (1H,m) 3.26 (1H, s), 3.35 (1H, d, J=15.5 Hz), 3.61 (1H, dd,J=10.4, 8.6 Hz), 3.69 (1H, d, J=15.5 Hz), 3.97 (1H, t, J=8 Hz), 5.84(1H, d, J=3.2 Hz), 6.35 (1H, dd, J=3.3, 1.8 Hz), 7.03-7.08 (2H, m),7.24-7.41 (5H, m), 7.43-7.49 (2H, m), 7.88 (1H, s).

EXAMPLE 18

(3R,5R,6S)-3-(2-(Oxazol-5-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane

This compound was prepared from the compound of Description 35 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.¹ H NMR (CDCl₃, 360 MHz), δ 1.65 (4H, m), 2.04 (1H, d), 2.21 (1H, dd,J=12.9, 8.3 Hz), 2.52 (1H, qn), 2.79 (1H, t, J=12.3 Hz), 3.20 (1H, d),3.54 (1H, s), 3.63 (1H, dd, J=10.1 8.7 Hz), 3.98 (1H, t, J=8.0 Hz), 6.59(1H, s). 7.07 (1H, d, J=8.6 Hz), 7.15 (1H, s), 7.30 (3H, m), 7.38 (1H,d, J=8.6 Hz). 7.43 (2H, m), 7.76 (1H, s). M/Z (ES+) 445 (M+H, 100%).

EXAMPLE 19

(3R,5R,6S)-3-(2-(5-Methylfur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 36 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.MS (ES) m/z 458 (M⁺ +1, 100%). ¹ H NMR (360 MHz, CDCl₃) d 1.66-1.75 (3H,m), 2.04-2.10 (1H, m), 2.21 (1H, dd, J=13.0 8.6 Hz), 2.29 (3H, s),2.39-2.44 (1H, m), 2.68-2.80 (2H, m), 3.31-3.36 (1H, m), 3.64 (1H, t,J=9.4 Hz), 3.86 (1H, d, J=11.2 Hz), 4.02 (1H, t, J=8.3 Hz), 5.60 (1H, d,J=2.9 Hz), 5.90 (1H, s), 7.02-7.04 (2H, m), 7.26-7.42 (4H, m), 7.58-7.60(2H, m).

EXAMPLE 20

(3R,5R,6S)-3-(2-(5-Methylisoxazol-4-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane

This compound was prepared from the compound of Description 37 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.MS (ES) m/z 456 (M⁺ +1, 100%). ¹ H NMR (360 MHz, CDCl₃) d 163-1.71 (3H,m), 1.87(3H,s), 2.02-2.06 (1H, m), 2.38-2.48 (1H, m), 2.76-2.84 (2H, m),3.33-3.38 (1H, m), 3.54 (1H, dd, J=10.4 9.0 Hz), 3.77 (1H, d, J=10.8Hz). 3.88 (1H, t, J=7.9 Hz), 6.98 (1H, d, J=9.4 Hz), 7.04-7.05 (2H, m),7.16-7.21 (2H, m), 7.37-7.41 (3H, m), 7.78 (1H, s).

EXAMPLE 21

(3R,5R,6S)-3-(Thiophen-2-yl-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane

This compound was prepared from the compound of Description 37 accordingto the method illustrated in Example 9 to afford the hydrochloride salt.MS (ES) m/z 460 (M+H, 100%). ¹ H NMR (D₂ O, 360 MHz), δ 1.44 (1H, t),1.74-2.04 (6H, m), 3.01 (1H, t), 3.16 (1H, t, J=9.2 Hz), 3.34 (1H, d),3.52 (1H, t), 3.99 (1H, s), 6.01 (1H, d, J=4.9 Hz), 6.13 (1H, s), 6.45(1H, d, J=8.4 Hz), 6.51 (1H, d), 6.86 (1H, s), 7.08 (1H, m), 7.18 (5H,m).

We claim:
 1. A compound of the formula (I): ##STR35## wherein R¹represents hydrogen, hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkylC₁₋₄ alkyl, fluoroC₁₋₆ alkyl, C₁₋₆ alkoxy, fluoroC₁₋₆alkoxy, C₁₋₆ alkoxyC₁₋₄ alkyl, C₁₋₆ alkoxyC₁₋₄ alkoxy, fluoroC₁₋₆alkoxyC₁₋₄ alkyl, C₂₋₆ alkenyloxy, C₃₋₇ cycloalkoxy, C₃₋₇ cycloaklylC₁₋₄alkoxy, phenoxy, benzyloxy, cyano, halogen, NR¹¹ COR¹⁴, NR^(a) R^(b),SR^(a), SOR^(a), SO₂ R^(a), OSO₂ R^(a), or C₁₋₄ alkyl substituted bycyano or CO₂ R^(a), R^(a) and R^(b) each independently representhydrogen, C₁₋₄ alkyl or fluoroC₁₋₄ alkyl;R² represents hydrogen,halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; or when R² is adjacent to R¹, theymay be joined together such that there is formed a 5- or 6-memberedsaturated or unsaturated ring containing one or two oxygen atoms; R³represents a 5- or 6-membered aromatic heterocyclic group containing 1,2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, whichgroup is optionally substituted by one or two groups selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, SR^(a), SOR^(a),SO₂ R^(a), COR^(a), CO₂ R^(a), phenyl, --(CH₂)_(r) NR^(a) R^(b),--(CH₂)_(r) NR^(a) COR^(b), --(CH₂)_(r) CONR^(a) R^(b), or CH₂C(O)R^(a), where R^(a) and R^(b) are each independently hydrogen or C₁₋₄alkyl and r is zero, 1 or 2; R⁴ represents hydrogen, halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano,SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl,C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, where R^(a) andR^(b) each independently represent hydrogen or C₁₋₄ alkyl; R⁵ representshydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl or C₁₋₆ alkoxysubstituted by C₁₋₄ alkoxy; R⁶ represents hydrogen, COR^(a), CO₂ R^(a),COCONR^(a) R^(b), COCO₂ R^(a), C₁₋₆ alkyl optionally substituted by agroup selected from (CO₂ R^(a), CONR^(a) R^(b), hydroxy, cyano, COR^(a),NR^(a) R^(b), C(NOH)NR^(a) R^(b), CONHphenyl(C₁₋₄ alkyl), COCO₂ R^(a),CONHNR^(a) R^(b), C(S)NR^(a) R^(b), CONR^(a) C₁₋₆ alkylR¹², CONR¹³ C₂₋₆alkenyl, CONR¹³ C₂₋₆ alkynyl, COCONR^(a) R^(b), CONR^(a) C(NR^(b))NR^(a)R^(b), CONR^(a) heteroaryl, and phenyl optionally substituted by one,two or three substituents selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, halogenand trifluoromethyl), where R^(a) and R^(b) are each independentlyhydrogen or C₁₋₄ alkyl; or R⁶ represents a group of the formula --CH₂C.tbd.CCH₂ NR⁷ R⁸ where R⁷ and R⁸ are as defined below; or R⁶ representsC₁₋₆ alkyl, optionally substituted by oxo, substituted by a 5-memberedor 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atomsoptionally substituted by ═O or ═S and optionally substituted by a groupof the formula ZNR⁷ R⁸ where Z is C₁₋₆ alkylene or C₃₋₆ cycloalkyl; R⁷is hydrogen or C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl,or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy or hydroxyl; R⁸ is hydrogen orC₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkylsubstituted by C₁₋₄ alkoxy, hydroxyl or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S; or R⁷, R⁸ and the nitrogen atom to which they are attached forma heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted byone or two groups selected from hydroxy or C₁₋₄ alkoxy optionallysubstituted by a C₁₋₄ alkoxy or hydroxyl group, and optionallycontaining a double bond, which ring may optionally contain an oxygen orsulphur ring atom, a group S(O) or S(O)₂ or a second nitrogen atom whichwill be part of a NH or NR^(c) moiety where R^(c) is C₁₋₄ alkyloptionally substituted by hydroxy or C₁₋₄ alkoxy; or R⁷, R⁸ and thenitrogen atom to which they are attached form a non-aromatic azabicyclicring system of 6 to 12 ring atoms; or Z, R⁷ and the nitrogen atom towhich they are attached form a heteroaliphatic ring to 4 to 7 ring atomswhich may optionally contain an oxygen ring atom; R⁹ and R¹⁰ eachindependently represent hydrogen, halogen, C₁₋₆ alkyl, CH₂ OR^(d), oxo,CO₂ R^(a) or CONR^(a) R^(b) where R^(a) and R^(b) are each independentlyhydrogen or C₁₋₆ alkyl and R^(d) represents hydrogen, C₁₋₆ alkyl orphenyl; R¹¹ represents hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy orhydroxyl; R¹² represents OR^(a), CONR^(a) R^(b) or heteroaryl, whereR^(a) and R^(b) are each independently hydrogen or C₁₋₄ alkyl; R¹³represents H or C₁₋₆ alkyl; R¹⁴ represents C₁₋₆ alkyl, C₁₋₆ alkoxy,fluoroC₁₋₆ alkyl or phenyl; p is zero or 1; q is 1 or 2; and the brokenline represents a double bond;or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 of the formula (Ia) or apharmaceutically acceptable salt thereof: ##STR36## wherein R¹, R², R³,R⁴, R⁹, R¹⁰ and the broken line are as defined in claim
 1. 3. Thecompound as claimed in claim 1 wherein R¹ is a methyl, trifluoromethyl,methoxy, ethoxy, isopropoxy or trifluoromethoxy group.
 4. The compoundas claimed in claim 1 wherein R² is a hydrogen, fluorine or chlorineatom.
 5. The compound as claimed in claim 1 wherein R³ is a groupselected from furan, pyridine, pyrazole, imidazole, oxazole, isoxazole,pyrazine, pyrimidine, thiazole, 1,2,3-triazole, 1,2,4-triazole,1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, each heteroaryl groupbeing optionally substituted as defined in claim
 1. 6. The compound asclaimed in claim 5 wherein R³ is the group ##STR37## where R¹¹ ishydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃, NO₂, CN, SR^(a),SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a), (CH₂)_(r) CONR^(a) R^(b),(CH₂)_(r) NR^(a) R^(b) or (CH₂)_(r) NR^(a) COR^(b), where R^(a) andR^(b) are hydrogen or C₁₋₄ alkyl, and r is zero, 1 or
 2. 7. The compoundas claimed in claim 1 wherein R⁴ is a hydrogen atom or a fluorine atom.8. The compound as claimed in claim 1 wherein R⁵ is a hydrogen atom. 9.The compound as claimed in claim 1 wherein R⁶ is a hydrogen atom or aC₁₋₆ alkyl group substituted by a 5-membered heterocyclic ringcontaining 2 or 3 nitrogen atoms as defined in claim
 1. 10. The compoundas claimed in claim 1 wherein R⁹ and R¹⁰ are both hydrogen atoms. 11.The compound as claimed in claim 1 wherein p is zero.
 12. The compoundas claimed in claim 1 wherein q is
 2. 13. The compound as claimed inclaim 1 wherein the double bond represented by the broken line isabsent.
 14. A compound which is selectedfrom:(6S,5R)-3-(5-methoxy-2-(5-trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;(6S,5R,3S)-3-(5-methoxy-(2-(5-trifluoromethyl)tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;(6S,5R)-3-(5-methoxy-2-(tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene;(6S,5R,3S)-3-(5-methoxy-2-(tetrazol-1-yl)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;(5R,6S)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene;(3S,5R,6S)-3-(2-fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;(3S,5R,6S)-6-phenyl-3-(2-(thiazol-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3S,5R,6S)-6-phenyl-3-(2-(thien-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-3-(2-(fur-3-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-6-phenyl-3-(2-(pyrid-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-6-phenyl-3-(2-(pyrid-3-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-6-phenyl-3-(2-(pyrid-4-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-6-phenyl-3-(2-(oxazol-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-6-phenyl-3-(2-(pyrazin-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-6-phenyl-3-(2-(pyrimidin-2-yl)-5-(trifluoromethoxy)phenyl)-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-3-(2-(fur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-(1,2,4-triazol-3-ylmethyl)-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-3-(oxazol-3-yl-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;(3R,5R,6S)-3-(2-(5-methylfur-2-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-3-(2-(5-methylisoxazol-4-yl)-5-(trifluoromethoxy)phenyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]decane;(3R,5R,6S)-3-(thiophen)-2-yl-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]decane;ora pharmaceutically acceptable salt thereof.
 15. The compound as claimedin claim 1 which has the sterochemistry shown in formula (Ic) ##STR38##wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, p, q and the broken line are asdefined in claim
 1. 16. The compound as claimed in claim 15 wherein thedouble bond represented by the broken line is absent and thestereochemistry of the 3-position is 3--(R).
 17. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 in associationwith a pharmaceutically acceptable carrier or excipient.
 18. A methodfor the treatment of physiological disorders associated with an excessof tachykinins, which method comprises administration to a patient inneed thereof of a tachykinin reducing amount of a compound according toclaim
 1. 19. A method according to claim 18 for the treatment of pain orinflammation, migraine, emesis or postherpetic neuralgia.
 20. A processfor the preparation of a compound as claimed in claim 1 whichcomprises:(A.1), where the broken line is absent, reducing a compound offormula (IIA) ##STR39## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, p and qare as defined in claim 1; (A.2), where the broken line is absent,reducing a compound of formula (IIB) ##STR40## using the reactionconditions described in process (A.1), above; or (B), where the brokenline is a double bond, reacting a compound of formula (III) ##STR41##wherein R⁴, R⁵, R⁶, R⁹, R¹⁰ and q are as defined in claim 1 and each R⁴⁵is a C₁₋₄ alkyl group, with a compound of formula (IV) ##STR42## whereinR¹, R², R³ and p are as defined in claim 1 and Hal is a halogen atom; or(C) reacting a compound of formula (V) ##STR43## wherein R¹, R², R³, R⁴,R⁵, R⁹, R¹⁰, p, q and the broken line are as defined in claim 1 with acompound of formula (VI):

    LG--R.sup.6a                                               (VI)

where R^(6a) is a group of the formula R⁶ as defined in claim 1 (otherthan H) or a precursor therefor and LG is a leaving group; and, ifR^(6a) is a precursor group, converting it to a group R⁶ ; or (D)interconversion of a compound of formula (I) to give another compound offormula (I); or (E), where p is zero and R³ is a tetrazol-1-yl group,reacting an of intermediate of formula (VII) ##STR44## with ammoniumchloride and sodium azide; or (F) a coupling reaction between a compoundof formula (VIII) and (IX) ##STR45## wherein one of R⁴⁰ and R⁴¹ isB(OH)₂ or Sn(alkyl)₃ or a derivative thereof, and the other is a leavinggroup; or (G) cyclising a compound of formula (X) ##STR46## wherein Y"is --CH₂ -- or --CH₂ CH₂ --; or (H), wherein X is --CH₂ -- and Y is--CH₂ -- or --CH₂ CH₂ --, reacting a compound of formula (XX) ##STR47##with a compound of formula (IV) wherein Hal in formula (IV) is chlorine,bromine or iodine, under the conditions of a reductive Heck reaction; or(J), where the dotted line is a double bond, dehydrating a compound offormula (XXI) ##STR48## each process being followed, whereby necessary,by the removal of any protecting group where present; and when thecompound of formula (I) is obtained as a mixture of enantiomers ordiastereoisomers, optionally resolving the mixture to obtain the desiredenantiomer; and/or, if desired, converting the resulting compound offormula (I) or a salt thereof, into a pharmaceutically acceptable saltthereof.